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Periodontology 2000, Vol. 0, 2017, 1–17 © 2017 John Wiley & Sons A/S.

y & Sons A/S. Published by John Wiley & Sons Ltd

Printed in Singapore. All rights reserved PERIODONTOLOGY 2000

Molecular basis for

immunohistochemical and
inflammatory changes during
progression of gingivitis to

Two common diseases – gingivitis and periodonti- molecular regulators of this critical process, which
tis – affect the periodontium. These diseases have involves a wide variety of interactions among dif-
been categorized and classified according to their ferent tissue compartments and is highly special-
clinical presentations and symptoms. The most ized in gingivae. The data that are available come
recent classification was proposed by the American primarily from animal studies and rely heavily on
Academy of Periodontology in 1999 (7). This classi- indirect evidence from markers of inflammation
fication, as in previous ones, is based on clinical, secreted into fluids, such as gingival crevicular flu-
radiographic and demographic data. Signs and ids, saliva and serum. These milieus for markers
symptoms of disease entities are used for distin- of disease are valuable and present opportunities
guishing various forms of gingivitis and periodonti- for development of preventive, epidemiological
tis of gingivitis and periodontitis. Information and therapeutic applications.
regarding the transition between disease forms, This knowledge is fundamental for understanding
such as the transition from gingivitis to periodon- the pathogenetic transition, molecular events, epi-
titis, is scarce. It has been proven that gingivitis demiological impact and development of therapeu-
follows a linear and progressive course when a tics. In the absence of such extensive knowledge,
healthy individual stops oral care, as shown by the periodontal diseases have been treated using the
experimental gingivitis model (82). However, such same methods and strategies, which aimed to elimi-
data for humans is limited and it is not known if nate soft and hard deposits using mechanical
and when gingivitis transforms into periodontitis. approaches, since the dawn of ‘modern’ dentistry in
The paradigm suggests that periodontitis has to the 18th century, aiming to eliminate soft and hard
follow gingivitis. However, it is virtually impossible deposits with mechanical terms (55). Meanwhile, our
to establish at which point this transition occurs understanding of the pathological processes inherent
as most patients present for dental care with to periodontal diseases is continuously evolving.
either gingivitis or periodontitis. A PubMed search Novel molecular techniques used to investigate, and
performed at the time of writing this article found insights into, the role of specific cell types involved
more than 300 publications on this the transition during the conversion of periodontal tissues from
from gingivitis to periodontitis. Of 200 publications health to disease warrant revision of the classification
in humans investigating the transition from gingi- of periodontal pathologies and development of a bio-
vitis to periodontitis, a very limited number pre- logical approach to treatment. This review focuses on
sent direct evidence on the histological changes the pathological changes that occur during the pro-
that occur over time and how they correlate to gression of gingivitis into periodontitis, discussing the
the clinical transition from gingivitis to periodonti- molecular, cellular and immunohistochemical
tis. Even more limited is our knowledge of the aspects of the inflammatory process.

Kurgan & Kantarci

Inflammatory changes during Microbiological, immunological and animal model

studies have shown that in the case of gingivitis,
periodontal disease progression
inflammation is limited to the soft tissues, epithelium
and connective tissue (15, 58, 106, 135). In the case of
Recognition and appreciation of periodontal diseases,
periodontitis, inflammatory processes extend to the
which occur in many disease forms, can be traced
supporting tissues, including the alveolar bone (13,
back to antiquity. Descriptions of clinical symptoms
32, 44, 104, 107, 114, 135). In both forms of periodon-
and how they can be treated were included in ancient
tal disease (chronic periodontitis and aggressive peri-
Egyptian and Chinese writings, suggesting that peri-
odontitis), the pathological consequences are
odontal diseases were known possibly 5,000 years
associated with the accumulation of bacteria at the
ago (42). Comprehensive written accounts of peri-
tooth surface, leading to a host response in which
odontal disease did not appear until the 18th century.
inflammatory cells infiltrate the periodontal tissue
It is clear from the work by Fauchard & Lindsay (29)
and by John Hunter that tooth loss and mobility were
Inflammation was first described by Celsus (116) as
associated with loss of ‘the gums, alveoli and teeth’.
a phenomenon that was the result of irritation, injury
For decades following these early ‘modern’ studies,
or infection of the tissues. Inflammation presents
the main debate around periodontal diseases was
with four cardinal signs, namely redness (rubor),
centered on the causes of pathologies (23, 85). Alveo-
swelling (tumor), heat (calor) and pain (dolor). The
lar pyorrhea was widely used to describe periodontal
fifth cardinal sign of inflammation (functio laesa) was
signs and symptoms (31). During the 18th century,
added by Galen (116) in the 2nd century AD, defining
two different disciplines emerged: the European dis-
a disturbance of function. This concept has been the
cipline of constitutional/systemic causes, according
paradigm for thousands of years. Based on this
to which ‘pyorrhea may and does exist independently
approach, disease development was defined as an
of foreign deposits’; and the North American disci-
imbalance in the inflammatory process (88, 89).
pline of local causes, according to which ‘pyorrhea’
With the identification of microorganisms and their
resulted from ‘a sequence of local causes. . . chiefly. . .
association with diseases, a germ theory was pro-
salivary calculus’ (23). While the debate dominated
posed in the late 19th century. As reported by
the 19th century, new histological techniques, dental
Medzhitov (95), Robert Koch and Louis Pasteur iden-
radiology and microbiology contributed to the under-
tified microorganisms as major inducers of the acute
standing of atrophy and degeneration of periodontal
inflammatory response. Metchnikoff (95) reported
tissues, occlusal trauma and infectious causes (23),
that phagocytosis of microbes and other host cells
suggesting that the primary etiological factors for
results in the resolution of acute inflammation. These
periodontal diseases are the microbial communities
studies are seminal in demonstrating: (i) the role of
and specific species (139).
microbial species as etiological factors for diseases,
‘Chronic periodontitis’ was appreciated as a major
(ii) the induction of inflammation by the host as a
periodontal disease as early as the 1960s. It was also
defense mechanism, (iii) the role of acute inflamma-
noted that this form of clinical disease occurred
tion, and (iv) the resolution of the inflammatory
almost universally, primarily affecting adults. Adult
response by the host’s own mechanisms. Therefore, it
periodontitis progresses at a slow and continuous
can be argued that our recent discoveries have all
rate, thus increasing in its impact with age (86).
stemmed from these early observations.
Another critical observation in the 1960s was that gin-
The inflammatory response is vital for our survival
givitis is the initial lesion for periodontitis (86). The
throughout life (59, 60). Inflammation regulates the
impact of this knowledge was remarkable because,
defense against pathogens and environmental stress,
for the first time, a link between two disease forms in
and controls wound healing. In response to an injury
the oral cavity was established. It was demonstrated
or infection, an acute inflammatory response occurs
that periodontal diseases can be experimentally
almost immediately (12). This phase is short-lived
induced and that progressive inflammation leads to
and usually results in complete healing and restora-
severe gingivitis (82). Oral plaque was identified as the
tion of homeostasis. Acute inflammation is now
primary etiologic factor in gingival inflammatory dis-
accepted to be a physiological response that occurs in
ease, and effective removal of plaque was observed to
vascularized tissues to defend the host and to main-
result in control of the disease (86). Interestingly,
tain homeostasis. In essence, inflammation is initi-
these studies also showed that not all forms of gingivi-
ated as a protective response to challenges with
tis resulted in periodontitis.

Progression of gingivitis to periodontitis

pathogens or foreign bodies, or to injury of host tis- in which inflammation is eliminateds (12). Various
sues. This process is characterized by vascular dila- macrophage phenotypes have recently been identi-
tion, enhanced permeability of capillaries and fied as M1 and M2 populations, in which polarization
increased blood flow and leukocyte recruitment (70). results in proinflammatory or proresolution phase
Polymorphonuclear neutrophils are the first leuko- macrophages (19, 43, 91).
cyte responders and accumulate at inflamed sites. In the context of periodontal pathogenesis, the
These cells are crucial, representing the first line of acute inflammatory stage usually goes unnoticed in
defense of the innate immune system and exert cases of gingivitis or an ongoing periodontitis. The
phagocytic and microbicidal functions (70, 87). exception is for periodontal abscesses, necrotizing
Monocytes migrate to the site of inflammation and ulcerative gingivitis or periodontal pathologies associ-
differentiate into macrophages. Macrophages have ated with nonoral diseases. Clinical signs and symp-
multiple roles: (i) they contribute to the phagocytosis toms associated with these acute periodontal diseases
and killing of bacteria and viruses, (ii) they clear cellu- are bleeding, pain, discoloration, odor and swelling,
lar debris and apoptotic neutrophils resulting from supporting the notion for the cardinal signs. How-
phagocytosis, (iii) they act as a bridge between innate ever, these forms of periodontal diseases are rare.
and acquired immunity by recruitment of lympho- When acute inflammation remains unresolved, it
cytes, and (iv) they release cytokines and present evolves into a chronic phase. Chronicity is a natural
antigens (99). Overall, multifunctional macrophages response of the inflammatory process and takes place
are primarily responsible for preventing prolonged as a result of insufficiency of the host’s immune and
inflammation. Through a noninflammatory process inflammatory responses in their capacity to remove

Fig. 1. Initial (A), early (B), established (C) and advanced metalloproteinase; OPG, osteoprotegerin; PGE2, prosta-
(D) stages of periodontal disease. fMLP, N-formylmethio- glandin E2; PMN, polymorphonuclear neutrophil; RANTES,
nine-leucyl-phenylalanine; IFN-c, interferon-gamma; IL, regulated on activation, normal T cell expressed and
interleukin; LPS, lipopolysaccharide; LT, Leukotriene; secreted; TIMP, tissue inhibitor of metalloproteinase; TNF-
MCP, monocyte chemoattractant protein; MIP, macro- a, tumor necrosis factor-alpha.
phage migration inhibitory factor; MMP, matrix

Kurgan & Kantarci

and clear the challenge (96). In the case of microbial demonstrate mainly vascular changes and infiltration
inducers of inflammation, microbes and their specific of neutrophils (80, 134, 137). Specific markers for
virulence structures/factors perpetuate the disease, adhesion molecules, as well as cytokines and chemo-
utilizing the body’s defense system as a medium for kines responsible for the chemotactic recruitment of
further colonization. The body tries to protect itself neutrophils (e.g. interleukin-8), can be seen. Minimal
against the pathogenic stimuli from bacteria or accumulation of bacterial moieties on dental surfaces
viruses by mounting a prolonged and chronic battle, is observed; the dentogingival attachment is intact.
which results in tissue destruction (87, 96). The bal- Sulcus epithelium shows formation of rete pegs,
ance between healing and destruction is delicate and possibly as a function of expansion of epithelial tissue–
depends heavily on how acute inflammation pro- connective tissue contact and vascular changes.
gresses into chronic inflammation.
Patients with periodontal disease usually present to
Early lesion
the dental office at this stage where either the inflam-
mation has become chronic and/or the periodontal The early lesion follows the initial lesion. It is charac-
tissues have undergone destruction. While a linear terized by an increased number of neutrophils in the
relationship between gingivitis and periodontitis is connective tissue and the appearance of macro-
well established in animal models and human epi- phages, lymphocytes, plasma cells and mast cells.
demiological data, it is not clear how the molecular Complement proteins are activated. The epithelium
processes regulate this transition. proliferates to form deeper rete pegs. Clinical signs of
In 1976, Page & Schroeder (104) classified the devel- gingival inflammation, such as bleeding, can be
opment of gingival and periodontal disease into four observed. Microbial biofilm extends and matures at
phases – initial, early, established and advanced – the subgingival level. The basal cell layer of the
based on clinical and histological findings. These epithelium starts to proliferate in an attempt to
observations still form the basis for understanding increase the physical barrier between the biofilm and
the different stages during progression (Fig. 1). the connective tissue migrating apically. Sulcus starts
deepening. Fibroblasts demonstrate signs of degener-
ation through apoptosis, and collagen fibers start to
Initial lesion
break down to provide space for leukocyte infiltration
The initial lesion is the response of resident leuko- (39, 67, 81, 83, 104, 125).
cytes and endothelial cells to the bacterial biofilm. At This stage is critical for recruitment of other cells
this stage, there are no signs of clinical inflammation, of the immune response. Macrophages dominate
but changes in tissues can be histologically assessed. the periodontal tissues and are the key players (28).
There is marked dilation of the vasculature, elevated Their role involves recruitment of large numbers of
hydrostatic pressure in the microcirculation and neutrophils and lymphocytes while phagocytizing
increased gaps between endothelial cells in the capil- and eliminating bacteria. Cytokine production
laries, all of which lead to increased permeability in increases, with higher levels of interleukin-1, inter-
the microvascular bed (57, 111). As a result, proteins, leukin-6 and tumor necrosis factor-alpha (10). These
and subsequently fluids, start to exude into the tis- cytokines are responsible for increasing the activa-
sues. Clinically, there is increased flow of gingival tion of inflammation and mounting a highly orga-
crevicular fluid that helps in diluting and washing nized inflammatory response (115). Meanwhile,
away harmful substances produced by the plaque chemokines, such as interleukin-8, macrophage
biofilm. inflammatory protein and RANTES, are produced
Neutrophils start migrating into the tissues affected and released into the gingival tissues and the gingi-
by periodontal disease as a result of activation of adhe- val crevicular fluid (136). These proinflammatory
sion molecules, such as intercellular adhesion mole- cytokines and chemokines are involved in further
cule-1 and endothelial adhesion molecule-1. recruitment of immune cells to the site of injury
Neutrophils follow a chemoattractant gradient, and bacterial insult (111). In an attempt to confine
formed by substances from plaque microflora and the actions of ‘proinflammatory’ cytokines and
host cells, to the gingival crevice (67, 104). Therefore, chemokines, macrophages and T-lymphocytes also
chemotaxis is a critical event at this early phase and start producing ‘anti-inflammatory’ cytokines, such
enables the migration of nonresident cells to the site as interleukin-4, interleukin-10 and interleukin-13.
of injury/insult through a dilated vessel wall. A There is no loss of dentogingival attachment, even if
histopathological analysis at this stage will the sulcus is deepened.

Progression of gingivitis to periodontitis

Established lesion connective tissue (65, 67). This results in widespread

manifestations of inflammation and immunopatho-
An established lesion can be considered as occurring
logical tissue damage. There is extensive degradation
after the period of full transition from the innate
of collagen fibers and more apical migration of junc-
immune response to the acquired immune response.
tional epithelium. The pocket deepens and the bio-
It represents a stage in which acute inflammation
film continues to grow apically in an anaerobic
cannot be arrested and resolved in an acute lesion, environment. At this stage, loss of connective tissue
and therefore the inflammation becomes chronic. In
attachment and bone occur (67, 78, 105).
addition to macrophages, plasma cells and T- and B-
In addition to the increases observed in cytokines
lymphocytes become dominant, with IgG1 and IgG3
and chemokines, there is an increase in tissue-
subclasses of B-lymphocytes also being present (124).
degradation products and mediators in the local
Blood flow is impaired, and collagenolytic activity is environment. Matrix metalloproteinases are abundant
increased (48). Collagen degradation continues and
and are associated with degradation of tissue integrity
the inflammatory cell infiltrate penetrates deeper into
(117). As in the previous stages of periodontal inflam-
the tissue. During this time, the dentogingival epithe-
mation, the mechanisms responsible for resolving the
lium continues to proliferate and the rete pegs pene-
inflammatory processes are activated. In addition to
trate deeper into the connective tissue in an attempt
the anti-inflammatory cytokines and chemokines, tis-
to maintain epithelial integrity and provide a barrier
sue inhibitors of matrix metalloproteinases are
to microbial entry (22). A histological specimen
expressed (20). The host attempts to limit the damage
obtained at this stage would reveal a lesion domi-
resulting from the inflammatory process through a
nated by lymphocytes (40).
repair mechanism in which growth factors responsible
The junctional epithelium is replaced with loosely
for tissue restoration by activation of fibroblasts are
adherent pocket epithelium that allows the bacterial produced. Fibroblasts deposit collagen moieties;
biofilm to migrate deep into the periodontal pocket.
osteoblasts are activated as a result of osteoclastic
The pocket epithelium is heavily infiltrated with
bone resorption (16, 103). RANKL and osteoprotegerin
leukocytes, predominantly neutrophils, and shows
regulate the bone turnover stage (38). The battle
increased permeability, allowing the passage of sub-
between repair and damage results in a chronic lesion
stances in and out of the connective tissue (48, 67,
in which periodontitis progresses slowly over a num-
83, 104).
ber of years.
Clinically, this stage represents moderate-to-severe
These studies clearly present an accurate descrip-
gingivitis with gingival bleeding and color and con-
tion of periodontal disease and its stages. The evi-
tour changes. Subgingival biofilm expands while the
dence was based strongly on histological observations
dentogingival attachment is still intact. There is no
from tissue biopsies at different phases of periodontal
evidence for destruction of the alveolar bone and lesions and describes in detail how histopathological
periodontal ligament. The lesion can persist as such
transitions underlie the clinical disease entities. To
and becomes chronic without evolving into periodon-
this end, the work by Page & Schroeder (1976) is semi-
titis or leading to the damage of hard tissues. Still, the
nal and has set the basis for the tissue-associated char-
gingival inflammation can be reversed with a full
acteristics of periodontal disease. Later studies
return to homeostasis if mechanical elimination of support these observations and contribute to our
the biofilm is successful (79). Therefore, in the
knowledge of cellular activities occurring during the
absence of damage to alveolar bone, exposure of
transition of gingivitis to periodontitis.
cementum and destruction of periodontal ligament,
Inflammation of gingival tissue is prerequisite for
the established lesion is reversible; thus, gingivitis can
the development of periodontitis (73, 123) but may
be treated without evolving into periodontitis.
not ultimately result in progression of gingivitis to
periodontitis (24). While in some sites or individuals,
gingivitis never progresses to periodontitis (5), data
Advanced lesion
indicate that periodontitis is always preceded by gin-
The advanced lesion of gingival inflammation is the givitis (104). It is also important to note that in the
final stage in which gingivitis leads to periodontitis. same individual some sites would progress to peri-
This stage should be considered as the stage in which odontitis, whereas others remain stable for years.
periodontal destruction is initiated and is irreversible. Therefore, there is also an element of site-specificity
The inflammatory cell infiltrate, which comprises pre- during the progression of gingivitis to periodontitis,
dominantly plasma cells, extends deeper into the of which the mechanisms are still unclear.

Kurgan & Kantarci

Molecular regulators of the As outlined above, the inflammatory process is a

natural defense mechanism used by the body to
immune response and periodontal
evade invaders and respond to harm. Resolution of
inflammation inflammation is also a natural process for restoring
homeostatic balance and occurs almost concomi-
Advancements in technologies have been accompa-
tantly with activation of the inflammatory response.
nied with a deeper understanding of the immune
While these two mechanisms seem to counteract
responses and the roles of cellular and molecular pro-
each other, in essence, the same cell types and molec-
cesses during periodontal inflammation. Although the
ular activation patterns regulate both activation and
exact pathways through which gingivitis progresses to
deactivation of the inflammatory responses (36).
periodontitis are not fully clear, recent data have
Therefore, the entire process of physio-pathological
demonstrated that pathological events are associated
transition and its stages present a rather dynamic,
with dynamic activation and resolution of inflamma-
overlapping and somewhat redundant series of
tion in periodontal tissues, similarly to other parts of
events. In contrast to the reductionist and staged
the mammalian body (121). The periodontium also
explanation of these events and cellular activities,
presents unique pathogenetic characteristics. The
which allow scientists to dissect the body’s response
periodontal environment – the site populated with the
to a variety of endogenous and exogenous insults, a
largest number of bacterial species in the body – har-
new paradigm shift is emerging by which these blocks
bors highly sophisticated interactions between bacte-
of information could be linked through a deeper per-
ria and host tissues (84). The tissues are never sterile,
even after meticulous cleaning using mechanical and
‘Omics’ of molecular signatures, based on techno-
chemical methods (127). This feature alone requires a
logical advancements (high-throughput analytical
highly specialized epithelial attachment apparatus
methods), has unveiled how the proteome, the tran-
around the teeth. The interface between the epithelial
scriptome, the lipidome and the peptidome regulate
layer and the underlying connective tissue is also
the body’s reaction to the microbiome (33). These
highly specialized owing to a continuous load of bac-
advances are being rapidly adopted in periodontal
teria and stimulation of the epithelial structures (11).
medicine through linking local and systemic events
The inner epithelium facing the dental surfaces lacks
that occur during the inflammatory process with a
keratinization and is highly active. The turnover rate
clear goal of identification of molecular targets to be
of the gingival epithelial layer is also high; in addition
utilized in developing novel therapies. Therefore,
to its barrier function, the epithelium is directly
while still at a very compartmental stage and relying
involved in immune defense by producing cytokines
strongly on dissected series of cell activities, a molec-
and chemokines (e.g. interleukin-8) (27). In addition
ular approach to the specific events during inflamma-
to all these special characteristics of the gingival soft
tion is warranted.
tissues, the dental environment is the only place in the
Although the inflammatory response is protective,
entire body where a living hard tissue (alveolar bone)
failure to remove noxious materials produced by neu-
communicates directly with the outside environment
trophils via phagocytosis, failure to clear apoptotic
(through teeth). Therefore, cementum and the peri-
inflammatory cells and a delay in apoptosis are char-
odontal ligament attachment present a highly unique
acteristic of a chronic and pathological lesion (36).
structure not found elsewhere. It is not surprising to
Incomplete elimination of leukocytes from a lesion in
see overlapping uncommon functions attributed to
susceptible individuals results in failure to resolve
periodontal tissues and cells. For example, gingival
acute inflammation, leading to chronic disease and
and periodontal ligament fibroblasts also participate
fibrosis (147). Failure to resolve inflammation and to
actively in the inflammatory response through the
return tissue to homeostasis results in neutrophil-
generation of cytokines (138). Likewise, their expres-
mediated destruction and chronic inflammation
sion of receptors for recognition of proinflammatory
(146). Neutrophil-mediated damage to the host’s own
and profibrotic stimuli differ from those in lung and
tissues is a major cause of human inflammatory
skin fibroblasts, resulting in a highly active regulation
pathologies, including arthritis, asthma, cancers, car-
of tissue turnover by the fibroblast phenotypes in the
diovascular diseases and periodontal diseases (63).
periodontium (30). Such a dynamic and unique envi-
These data therefore indicate that resolution of
ronment also presents a highly complex network of
inflammation is critical for preventing chronicity and
interactions during the inflammatory process. The
that the window of opportunity for treatment based
molecular basis for these events is being elucidated.

Progression of gingivitis to periodontitis

on resolving the inflammatory process presents early In addition to the nonspecific innate immune
and relies on the actions of primary cells of the response, the body is able to acquire more specific
immune defense, such as phagocytes. adaptive responses to injury or inflammation (50). In
The main goal of the immune response is to detect these, pathogens are recognized, thereby allowing a
and eliminate pathogens or foreign invaders, such as stronger response should the pathogen present again
microorganisms (commonly called germs; namely in the future. Acquired (adaptive or specific) immu-
bacteria, viruses and fungi), parasites (such as nity is not present at birth; it is learned and only
worms), cancer cells and even transplanted organs found in most complex animals. As a person’s
and tissues (4). A typical immune response consists of immune system encounters foreign substances (anti-
four components: inflammatory inducers; the detect- gens), the components of acquired immunity learn
ing sensors; downstream mediators; and the target the best way to attack each antigen and begin to
tissues that are affected. The type and the degree of develop a memory for that antigen. Acquired immu-
inflammatory response activated are dependent on nity is also called specific immunity because it tailors
the nature of the inflammatory trigger (bacterial, viral its attack to a specific antigen previously encoun-
or parasitic) and its persistence (95). In response to tered. Its hallmarks are its ability to learn, adapt and
an infectious or inflammatory trigger, two types of remember (26).
immune responses are stimulated: innate and adap- Acquired immunity takes time to develop after the
tive. The innate immune system is present at birth first exposure to a new antigen. Thereafter, the anti-
and does not have to be learned through exposure to gen is remembered, and subsequent responses to
an invader (3). It thus provides an immediate that antigen are quicker and more effective than
response to foreign invaders. Its components treat all those that occurred after the first exposure. When an
foreign invaders similarly, recognizing only a limited injury occurs, there is a proliferation of antigen-speci-
number of identifying substances (antigens) or pat- fic T- and B-cells. T-cells recognize the foreign anti-
terns on foreign invaders. These antigens are present gen and specifically target it, which stimulates B-cells
on many different invaders (2, 3, 34, 41). Therefore, to produce antibodies against the antigen. T- and B-
pattern recognition is key for activating innate immu- cells assist macrophages and help to generate killing
nity. cells that mount a response.
Ontogenically, innate immunity is the oldest and
simplest mechanism that has been retained during
Pattern recognition and toll-like
the evolution of the host response in animals
(118). Even the simplest animals species have one
form of innate immune defense mechanism, Host–pathogen interactions occur through the recog-
demonstrating the importance of innate immunity nition of conserved molecular patterns called patho-
for survival of the species (14). This evolutionary gen-associated molecular patterns. Receptors that
insight also emphasizes the complexity and perfec- recognize these pathogen-associated molecular pat-
tion that the cells and the molecular mechanisms terns are germline encoded and are called pattern
of the innate immunity have reached. Innate recognition receptors (17, 18, 60, 69).
immunity, unlike acquired immunity, has no Toll-like receptors belong to the class of signaling
memory of the encounters, does not remember pattern recognition receptors (97) and comprise a
specific foreign antigens and does not provide any family of pattern recognition receptors named after
ongoing protection against future infection (110). their similarity to the Drosophila toll protein (76, 94).
It acts through the recruitment of immune cells, Their discovery, in the late 1990s, has sparked a resur-
activation of the complement system, identification gent interest in innate immunity. Indeed, the study of
and removal of foreign substances and activation toll-like receptors has helped in understanding the
of the adaptive immune system (34). economical specificity of the innate immune system
Phagocytic cells (neutrophils, monocytes and and that adaptive immunity did not evolve to replace
macrophages) are the cellular components of innate innate immunity, but rather evolved around it (61,
immunity. They trigger the release of chemical medi- 66).
ators, such as cytokines, that activate systems such as Toll-like receptors are transmembrane glycopro-
the complement system and the acute phase teins comprising an N-terminal leucine-rich repeat
response. These systems assist antibodies in clearing domain, a transmembrane region and a C-terminal
pathogens or mark them for destruction by other cells cytoplasmic signaling domain (61, 66). These recep-
(45, 47). tors are primarily expressed by first-line professional

Kurgan & Kantarci

phagocytes (e.g. neutrophils, macrophages and den- reperfusion injury, allergy and periodontitis. Toll-like
dritic cells) and are thus strategically located for early receptor 4 utilizes both myeloid differentiation pri-
recognition of microbial pathogens (1). To date, 10 mary response protein MyD88-dependent and toll/in-
human toll-like receptors have been identified that terleukin-1 receptor domain-containing adapter-
generally sense and respond to distinct types of inducing interferon-beta-dependent pathways (102)
microbial structures. (Fig. 2). It also undergoes dimerization with toll-like
Periodontitis is an infection-driven chronic inflam- receptor 2 that results in additional activation of toll-
matory disease, and toll-like receptors play a pivotal like receptor 4 (102). Toll-like receptor signaling occurs
role in its pathogenesis (46). Recent research has sug- via two different pathways – myeloid differentiation
gested that toll-like receptors are essential in main- primary response protein MyD88-dependent and -
taining the periodontium in a healthy state. When independent pathways (49). Toll-like receptors 1, 2, 4,
excessively activated or inadequately controlled, they 5, 6, 7, 8 and 9 utilize the myeloid differentiation pri-
may contribute to chronic inflammatory diseases and mary response protein MyD88-dependent pathway.
autoimmune diseases (46). Toll-like receptors play a Toll-like receptors 3 and 4 utilize the myeloid differen-
key role in chronic inflammation and autoimmunity tiation primary response protein MyD88-independent
by inducing the production of high levels of proin- pathway or toll interleukin-1 receptor domain contain-
flammatory cytokines (71, 98). Periodontal health ing adaptor-inducing interferon-beta pathway.
represents a dynamic state; hence, proinflammatory The myeloid differentiation primary response
and anti-inflammatory activities have to be optimally protein MyD88-dependent pathway is analogous to
balanced. When this homeostasis is disturbed by pathways signaling through interleukin-1 receptors.
pathogens, toll-like receptors become activated. Myeloid differentiation primary response protein
Gingival epithelial cells express toll-like receptors 2, MyD88 recruits interleukin-1 receptor-activated
3, 4, 5, 6 and 9, which are also the first to detect micro- kinase 4, which facilitates interleukin-1 receptor-
bial invasion. Once these toll-like receptors bind to activated kinase 4-mediated phosphorylation of
their respective pathogen-associated molecular pat- interleukin-1 receptor-activated kinase 1. Activated
terns, antimicrobial peptides and proinflammatory interleukin-1 receptor-activated kinase 4 associates
cytokines are released (49). If the microbial attack is with tumor necrosis factor receptor-associated
uncontrolled, excessive stimulation of toll-like receptors family six, leading to two distinct signaling path-
and increased production of proinflammatory cytoki- ways. One pathway leads to activation of protein-1
nes occur, leading to tissue destruction (49). Once the through mitogen-activated protein kinases. The
epithelial barrier becomes breached by pathogens and other pathway activates the inhibitor of nuclear
their cytotoxic products, toll-like receptors present on factor-jB kinase complex, which causes degrada-
nonimmune cells, such as fibroblasts, osteoblasts and tion of inhibitor of nuclear factor-jB, leading to
osteoclasts, also become activated (49). As a result, nuclear translocation of the transcription factor
pooling of cytokines occurs, further contributing to the nuclear factor-jB. Activation of both protein-1 and
destruction of periodontal tissues. Thus, uncontrolled nuclear factor-jB induce the production of proin-
activation of toll-like receptors results in a destructive, flammatory cytokines (6, 143).
rather than a protective, response (49).
Toll-like receptor 2 is readily detectable in gingival
Nuclear factor-jB signaling
epithelia, being denser in the spinous epithelial layer
than in the basal layer (71). There is up-regulation of Toll-like receptors serve as important signal-transdu-
toll-like receptors 2, 4, 7 and 9 (but not of toll-like cing elements, which alert the host through pattern
receptor 5) in periodontitis lesions (98). Toll-like recognition of diverse microbial products. Moreover,
receptor 4 plays a pivotal role in the pathogenesis of development of adaptive immunity is controlled
periodontitis. Lipopolysaccharides are the major viru- through activation of toll-like receptors present on
lence factor of gram-negative bacteria and putative innate immune cells. This activation results in the
periodontal pathogens, such as Porphyromonas gingi- production of cytokines and chemokines critical for
valis (49). Toll-like receptor 4 binds to lipopolysaccha- T-cell priming and differentiation. Toll-like receptors
ride with the help of lipopolysaccharide-binding bind to pathogen-derived factors and also to products
protein, lymphocyte antigen 96 (also known as MD2) of inflamed tissue (Fig. 3), thus activating transcrip-
and cluster of differentiation 14, and plays an impor- tion factors, such as nuclear factor-jB and the inter-
tant role in various immune and inflammatory dis- feron regulatory factors, which leads to the induction
eases, such as sepsis, rheumatoid arthritis, ischemia/ of immune and inflammatory genes and thereby to

Progression of gingivitis to periodontitis

Fig. 2. Toll-like receptors activation can be mediated by interleukin; IRAK 1/4, interleukin-1 receptor-activated
multiple pathways that are dependent on, or independent kinase-1/4; LPS, lipopolysaccharide; MAK, serine/thre-
of, the myeloid differentiation primary response protein onine protein kinase MAK; MAPK, mitogen-activated pro-
MyD88, which determines the type of ligand that binds to tein kinase; MyD88, myeloid differentiation primary
the toll-like receptor. Different lipopolysaccharide moieties response protein MyD88; NF-jB, nuclear factor-jB; TLR,
produced by various periodontopathogens differentially toll-like receptor; TNF-a, tumor necrosis factor-alpha;
regulate the activation of toll-like receptors. AP-1, activator TRAF-6, tumor necrosis factor receptor-associated factor 1.
protein-1; IKK inhibitor of nuclear factor-jB kinase; IL,

the release of inflammatory cytokines and type I the nuclear factor-jB pathway occurs in the presence
interferons (143). of many proinflammatory mediators (such as bacte-
Nuclear factor-jB was first identified as a transcrip- rial lipopolysaccharide, tumor necrosis factor-alpha,
tion factor that binds to a 10-base pair DNA element interleukin-1, matrix metalloproteinases, cyclooxyge-
in kappa immunoglobulin light-chain enhancer in B- nase-22 and inducible nitric oxide synthase), when
cells (128). The nuclear factor-jB family consists of these mediators are present in large quantities in tis-
five members: REL-a (p65); nuclear factor-jB1 (p50; sues with periodontal disease.
p105); nuclear factor-jB2 (p52; p100); c-REL; and In vitro studies have established that P. gingivalis
REL-b24. These members, except for REL-b24, form and other pathogenic periodontal bacteria can acti-
homodimers and heterodimers to produce nuclear vate nuclear factor-jB in periodontal tissues (77).
factor-jB transcription factors. The most common Several products associated with nuclear factor-кB
activating form in inflammatory reactions is a hetero- activation (especially interleukin-1, tumor necrosis
dimer of p50 and p65. They bind to the nuclear fac- factor-alpha and RANKL) are found in abundance
tor-jB 5`–3` site and then activate or repress in the diseased periodontium (8). RANKL mediated
transcription of the target gene (25). The key regula- osteoclastogenesis plays a pivotal role in inflamma-
tors of nuclear factor-jB are inhibitors of nuclear fac- tory bone resorption (142) and the process occurs
tor-jB, of which the most common are inhibitor of as a result of the enhanced concentration of
nuclear factor-jBa, inhibitor of nuclear factor-jBb RANKL and interleukin-1beta in periodontally dis-
and inhibitor of nuclear factor-jBe24. eased tissues. The activation of nuclear factor-jB in
The nuclear factor-jB family of transcription fac- the presence of such a diversity of biologically
tors has been shown to be involved in many different active molecules is a consequence of the activation
pathways and has a central role in regulating the of other signaling pathways, including mitogen-acti-
expression of a wide variety of genes that control both vated protein kinase and toll-like receptor path-
innate and adaptive immune responses. Activation of ways.

Kurgan & Kantarci

Fig. 3. Nuclear factor-jB signaling is key to the activation gamma; IL, interleukin; IRAK 1/4, interleukin-1 receptor-
of downstream events of toll-like receptor, regulating criti- activated kinase-1/4; LPS, lipopolysaccharide; MyD88,
cal events for the survival and function of immune cells myeloid differentiation primary response protein MyD88;
during the inflammatory transition of gingivitis to peri- NF-jB, nuclear factor-jB; P, Phosphate; p50, transcription
odontitis. 3a; Ik, inhibitor of kappa; IkB, inhibitor of kappa factor p50; p65, transcription factor p65; TAK1, transform-
B; IKK-a, inhibitor of nuclear factor-jB kinase subunit ing growth factor-beta-activated kinase 1; TLR, toll-like
alpha; IKK-b, inhibitor of nuclear factor-jB kinase subunit receptor; TRAF-6, tumor necrosis factor receptor-asso-
beta; IKK-c, inhibitor of nuclear factor-jB kinase subunit ciated factor 1; Ub, Ubiquitin.

mitogen-activated protein kinase cascade consists of

Mitogen-activated protein kinase
a series of three tiered protein kinases, namely a
mitogen-activated protein kinase and two upstream
Mitogen-activated protein kinases are an evolutionar- components (mitogen-activated protein kinase
ily conserved family of protein kinases that mediate kinase and mitogen-activated protein kinase kinase
fundamental biological processes and cellular kinase) (Fig. 4).
responses to different extracellular stimuli through Activation of the mitogen-activated protein kinases
multiple receptors (141). Mitogen-activated protein results in phosphorylation of specific transcription
kinases are involved in signal transduction of extra- factors that mediate gene transcription. Multiple
cellular hormones, growth factors, cytokines, bacte- interactions between the different mitogen-activated
rial antigens and environmental stresses, and play a protein kinase cascades serve to integrate the
crucial role in many aspects of immune-mediated responses and activate separate sets of genes (100,
inflammatory responses (64, 100). The three main 108). All three mitogen-activated protein kinase fami-
subfamilies of mitogen-activated protein kinases are lies are expressed in periodontal disease (113). During
extracellular-regulated kinases 1/2, c-Jun N-terminal initial interaction of pathogens with the host’s
activated kinases and p38. Although extracellular- immune system, pathogen-associated molecular pat-
regulated kinases are traditionally considered as terns, such as lipopolysaccharide, peptidoglycans,
being primarily activated by mitogens and growth lipoteichoic acid or bacterial CpG-DNA, can trigger
factors, and inducers of stress and proinflammatory cells of the innate immune system (149).
cytokines are activated by c-Jun N-terminal activated Cytokines produced in response to this initial
kinases and p38 (72), this general concept does not activation by pathogen-associated molecular pat-
apply to all cell types and to all external stimuli. terns can also activate signal transduction path-
However, there is evidence of cross-activation and ways by autocrine or paracrine mechanisms. These
interaction between various levels of the main microbial products and cytokines (e.g. interleukin-
mitogen-activated protein kinase pathways (extracel- 1beta and tumor necrosis factor-alpha) act through
lular-regulated kinase and p38) (112, 119). The the toll/interleukin-1 receptor family or the tumor

Progression of gingivitis to periodontitis

Fig. 4. Mitogen-activated protein kinases are important protein Elk1; ERK, extracellular signal-regulated kinase;
mediators of signal transduction in gingival and periodon- JNK, c-Jun N-terminal activated kinase; MAPK, mitogen-
tal tissues and are ubiquitously expressed in multiple cell activated protein kinase; MAPKK, mitogen-activated pro-
types. Their role during the progression of inflammation in tein kinase kinase; MAPKKK, mitogen-activated protein
periodontal diseases is to transmit the impact of extracellu- kinase kinase kinase; MEK, mitogen-activated protein
lar hormones, growth factors, cytokines, bacterial antigens kinase kinase; MEKK, mitogen-activated protein kinase
and environmental stresses, on the target cells, to transcrip- kinase kinase; MKK, MAP kinase kinase; p38, p38 mitogen-
tion factors, thus regulating the response of periodontal activated protein kinase; RAF, a serine/threonine-protein
cells to challenges. AP-1, activator protein-1; ATF-2, activat- kinase; TAK, transforming growth factor-beta-activated
ing transcription factor-2; ELK1, ETS domain-containing kinase.

necrosis factor receptor family. Activation of these Outcomes of periodontal

receptors triggers the mitogen-activated protein inflammation
kinase pathway, leading to activation of the tran-
scription factor nuclear factor-jB, which is known The inflammatory process results in various out-
to be required for expression of cytokine genes comes: (i) chronicity and extension of the inflamma-
(108). Activation of the mitogen-activated protein tory damage, (ii) fibrosis and scar formation, and (iii)
kinase/nuclear factor-jB pathway is key in the resolution and full restoration of homeostasis. As
development of chronic inflammatory conditions, described above in detail, unresolved acute inflamma-
such as rheumatoid arthritis and periodontal dis- tion leads to a chronic inflammatory response and
ease (75, 142). p38 activation leads to increased eventually to tissue damage by the host’s own defence
expression of various cytokine genes by modulat- mechanisms. Chronicity is critical for survival if the
ing both transcriptional and post-transcriptional early events in the immune-system response are
mechanisms. insufficient to eradicate the invaders. Through chronic
The contribution of each mechanism to the global inflammation, the body mounts the elements of
change of gene expression varies with cell type and acquired immune-defence mechanisms, leading to
the nature of external stimulation, but among the development of an extensive and sophisticated net-
genes that are at least partially modulated by post- work of cells (including lymphocytes), processes such
transcriptional mechanisms involving modification of as antigen presentation and specific defence systems
RNA-binding proteins as substrates of p38 mitogen- (for example, antibody production). While these
activated protein kinase are tumor necrosis factor- defence systems are designed to eliminate the specific
alpha, interleukin-8, interleukin-6, interleukin-2 and bacteria and their products, they are also responsible
cyclooxygenase-2 (38, 69, 94). Other genes are primar- for an inherent immunization with memory for future
ily regulated by transcriptional mechanisms and challenges with specific antigenic molecules. There-
include interleukin-1beta, RANKL, chemokines and fore, chronicity of the inflammation is essential
metalloproteinases (56, 109, 148). because it allows the host to evolve molecular defense

Kurgan & Kantarci

tools for future infections. Meanwhile, the same path- inflammation. Inadequate resolution and failure to
ways result in damage of the host’s own tissues. return tissue to homeostasis result in neutrophil-
In the periodontal organ, the proximity of different mediated destruction and chronic inflammation
tissue compartments leads to a complex system for (146) with destruction of extracellular matrix and
tissue turnover. Hard tissues, such as the alveolar bone, scarring and fibrosis (149). Scarring and fibrosis
bone and cementum, are bound with the periodontal in periodontitis prevent the return of tissue to home-
ligament, a connective tissue exposed to all cellular ostasis (147). Recent studies over the past decade,
and humoral activities of inflammation. Therefore, from our laboratory and others, have demonstrated
osteoimmunological mechanisms regulate the that resolution of periodontal inflammation results
response of alveolar bone to inflammatory changes not only in the prevention of further damage but also
(64). The result is loss of attachment and destruction in the regeneration of lost tissues and attachment (62,
of the alveolar bone and periodontal integrity. 74, 144). Even more recently, we have published data
Fibrotic changes occurring as a result of inflamma- suggesting that resolution of periodontal inflamma-
tion caused by specific drugs or genetic conditions as tion contributes to the resolution of inflammatory
etiologic agents are limited to the gingival tissues (9). pathologies in distant organs such as cardiovascular
These processes have been recently reviewed else- systems (148).
where in detail. Scarring is not common in oral tis- Various lipid inflammatory mediators derived from
sues (120). The reasons for the lack of scarring or arachidonic acid have been identified as crucial ‘re-
extensive fibrotic changes in gingival tissues, in the solvers’ in the early stages of the inflammatory pro-
absence of drugs and genetic conditions as etiologic cess (52). During inflammation, neutrophils are
agents, are not clear. In other organ systems, fibrosis produced that have generally beneficial effects in
is the result of extensive deposition of collagen and countering disease, but in the longer term, or if mal-
other extracellular matrix proteins, and reduced col- functioning, they may eventually result in trauma and
lagenase activity. This process is observed at low tissue damage through infiltration into tissues. Con-
levels during the late stages of gingival inflammatory sequently, a well-integrated inflammatory response
lesions where fibroblasts have increased activity in an and an intrinsic process for resolution are essential to
attempt to limit the inflammatory damage. The trans- re-establish homeostasis.
forming growth factor-beta1 pathway and CCN2/C- Lipoxins, which are described as a series of short-
transforming growth factor regulate the fibrotic lived anti-inflammatory lipid mediators, are endoge-
changes in tissues (122). While this mechanism has nously produced eicosanoids (51, 53). Lipoxin sig-
been clearly demonstrated in human gingival tissues naling at sites of inflammation regulates resolution
during gingival overgrowth and supports the notion of the inflammation through the ALX/FPR2 receptor
that the cellular regulators exist, it is highly unlikely and effectively inhibits the activation of nuclear fac-
that periodontal inflammation results in fibrosis. tor-jB light polypeptide gene enhancer in B-cells,
Likewise, scarring, which represents incomplete chemotaxis (and thus migration of inflammatory
healing and a form of fibrotic change, does not domi- cells out of the vasculature) and the generation of
nate wound healing as part of the pathological pro- oxygen radicals. Lipoxins regulate macrophages in
cess. Possible mechanisms preventing the oral tissues their phagocytosis of apoptotic cells. During acute
from becoming fibrotic or scarred are continuous inflammation, proinflammatory cytokines, including
stimulation of the innate immune response by micro- interleukin-1beta and interferon-gamma, can induce
bial moieties, incessant mechanical stimuli by the the production of lipoxins and anti-inflammatory
teeth and soft tissues or the presence of saliva in the cytokines (e.g. interleukin-4) that link the progres-
oral cavity. However, there is no clear evidence sion and the resolution of the inflammatory
regarding whether any of these processes are involved response (133).
in, and control, the fibrotic changes in the gingiva. Recent studies from our laboratory (92, 126, 131)
Resolution of the inflammatory process, as and others (35, 52, 54, 145) have reported intrinsic
described above, is also part of the activation phase. biochemical pathways that occur in exudates from
Once inflammation is activated, the body initiates resolving inflammatory tissue. The pathways were
resolution in order to prevent damage to the host’s shown to generate a new family of locally acting
own tissues. The goal of resolution is to restore home- mediators from the omega-3 polyunsaturated fatty
ostasis and return the tissue integrity to normal with- acids, eicosapentaenoic acid and docosahexaenoic
out permitting any damage (144). Thus, resolution of acid (129). Resolvins and protectins control the dura-
the inflammatory process is the desired outcome of tion and the magnitude of inflammation. They are

Progression of gingivitis to periodontitis

produced by enzymatic actions of the cyclooxyge- neutrophils and monocytes were identified. Whole
nase-2 pathway, particularly related to chemical reac- blood from subjects with localized aggressive peri-
tions in the presence of aspirin (35). Unlike other odontitis was shown to contain significantly lower
nonsteroidal anti-inflammatory drugs, aspirin has amounts of lipoxin A4 compared with blood from
unique characteristics. Aspirin acetylates cyclooxyge- periodontally healthy subjects. These preliminary
nase-2 to inhibit further production of prostanoids findings suggest compromised resolution pathways in
from arachidonic acid metabolism, but the acetylated subjects with aggressive periodontitis, which may
cyclooxygenase-2 has new enzyme activity as a 15- contribute to periodontal disease progression.
epi-lipoxygenase. This alternative pathway leads to
the synthesis of 15-R-hydroxy-(p)-eicosatetraenoic
acid. This molecule is transformed into 5 (6)-epoxyte- Conclusion
traene with the help of 5-lipoxygenase, and the pro-
duct is 15-epi-LXs or aspirin-triggered lipoxins (130). Periodontal inflammation affects not only the soft tis-
Aspirin-triggered lipoxin, the epimer of native lipoxin, sues of the periodontium but also the hard tissues of
possesses more powerful pro-resolving properties alveolar bone and dental cementum. Histopathologi-
than native lipoxin (130, 132, 140). cal evidence suggests that gingivitis follows a linear
These anti-inflammatory lipids reduce the cellular progress. It is not clear how and if gingivitis trans-
component of inflammation by inhibiting the pro- forms into periodontitis. Periodontitis follows gingivi-
duction and transportation of inflammatory cells and tis; gingivitis is a risk factor for periodontitis (73). This
chemicals to the sites of inflammation (148). Resol- knowledge is critical for understanding the patho-
vins and protectins can remove chemokines that are genetic transition, molecular events, epidemiological
generated in the inflamed tissues from apoptotic neu- impact and development of therapeutics. The data on
trophils and T-cells, as part of the molecular mecha- the pathological processes inherent to periodontal
nisms of resolution (101). Subsequently, in the body’s diseases is continuously evolving. Molecular path-
commitment to return tissues to health, the lipoxins, ways regulating periodontal inflammation also deter-
resolvins and protectins, and maresins, promote mine the outcomes of disease and healing. Treatment
active resolution of the inflammation through the of inflammatory diseases, and particularly periodon-
removal of leukocytes and other cellular debris, mak- titis, in which extensive tissue damage could result
ing them part of the molecular mechanisms that con- from the inflammatory process, needs to target a full
tribute to the restoration of tissue integrity once the restoration of the tissues lost. This can only be
need for the inflammatory response subsides (21, 54). accomplished by a thorough understanding of activa-
These findings changed the paradigm of resolution tion and resolution and of the molecular events that
from the concept of a passive process of the host to take place during these phases.
an active, regulated process controlled by specific
molecular entities that resolve inflammation. Thus,
this family of molecules appears to have an important Acknowledgments
role in regulating and inhibiting the harmful effects of
continued inflammation and represents biomolecules This work was supported in part by NIH/NIDCR grant
derived from the arachidonate pathway that oppose DE020906.
the effects of some of the proinflammatory eicosa-
noids with a likely impact on periodontal disease
(146). Consequently, it appears obvious that these References
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