Immunomodulation of periodontitis with SPMs

Introduction

Natural resolution of inflammation and specialized pro-resolving mediators

The acute inflammatory response may be divided into activation and resolution phases. Over time, evidence has accrued to suggest that the latter is not merely a passive process of chemoattractant and chemokine dilution which “fizzles out” after a while, but an active, programmed host response that “switches on” as the inflammatory lesion matures (7) that is mediated by a new class of eicosanoids collectively termed Specialized Proresolving Mediators (SPMs) (8–14). The discovery of this family of compounds introduced a fresh understanding of the inflammatory process, its development and indeed its resolution. Naturally, this led to a re-examination of previously established concepts surrounding disease etiology and treatment approaches. Building on previous knowledge, it is understood that the in vivo production of a mediator needs to be adequate to incite bioactions (11). The SPMs include resolvins, maresins, protectins and lipoxins that are derived from dietary Omega-3 polyunsaturated fatty acids (n-3 PUFA) or in the case of lipoxins, from endogenous arachidonic acid from cell membranes (15). Hence the concept of “good and laudable pus” which acknowledged the fact that pus contained the means to produce the resolution of inflammation. This family of compounds play an essential role in host defense by virtue of initiating the trafficking of leukocytes (16), a process known to be integral to the inflammatory response.

Upon challenge by a noxious stimulus, changes in blood flow, influx of neutrophils and edema are stimulated by prostaglandins and leukotrienes (17, 18). These processes manifest at a macro-level as the cardinal signs of inflammation. As the host inflammatory response builds up to this challenge, the pro-resolving mediators, maresins, protectins, resolvins and lipoxins along with their respective aspirin triggered (AT) variants undergo synthesis during the active phase of resolution (19, 20). It is imperative to recognize the synergy between the upregulation of pro-inflammatory elements of the response and the development of the resolution response itself.

The acute phase of inflammation may involve a microbial stimulus or one that is elicited because of the host's immune response to other forms of injury or insult. This is followed by local PUFA release from phospholipids found in cell membranes or their delivery to inflammatory sites by means of edema which would further result in the conversion of these PUFAs to specialized mediators (21).

Eicosanoids are produced from arachidonic acid within minutes of the initial insult (Figure 1). It is these leukotrienes and prostaglandins that signal neutrophils to arrive at the relevant site. Neutrophil availability is a function of LTD₄ and LTC₄ which impact vascular permeability, along with PGI₂ and PGE₂ which then affect blood flow (6, 22). As these products regulate neutrophil presence at the site of inflammation, the latter in turn tend to follow a transmigration gradient dictated by LTB₄ (23). Once it is ensured that the right cells (neutrophils) are at the right place, neutrophil induction is mediated by these eicosanoids along with other immune system components such as the complement system, chemokines and cytokines (24, 25). It is relevant to understand these early events in the inflammatory phase since they are responsible for the subsequent lipid class-switching that occurs when the arachidonic acid metabolic system changes from leukotriene production to that of pro-resolving mediators such as lipoxins (26). If unencumbered, this process results in the natural resolution of inflammation wherein the acute phase proceeds to resolution (Figure 2).

The resolution response tends to get delayed in the event of an interruption with lipoxin production or of the availability of receptors for this family of compounds (27, 28). It is the acute inflammatory response that signals the development of the resolution phase. Essential fatty acids in the diet such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) supplement the endogenous arachidonic acid-based system where these n-3 PUFA have been demonstrated to enzymatically (LOX-dependent) produce SPMs (Figure 3).

Thus, the production of these stereoselective products has been demonstrated via multiple pathways, which can be broadly categorized as intrinsic and extrinsic. The former includes SPM synthesis within the host in the absence of an external stimulant whereas the latter necessitates an external influence to the process. The intrinsic mechanisms for SPM production are varied based on enzyme mediators. One of these involves native enzymes, such as 12-LOX (platelet-derived) and 5-LOX (leukocyte-derived or 15-LOX (eosinophil-, monocyte- or epithelial cell-derived) and 5-LOX (leukocyte-derived) to produce lipoxins (21, 29, 30).

The extrinsic mechanism involves the modification of native enzymes by other compounds, such as aspirin. Even though aspirin inhibits the production of prostaglandins, it does so through a unique mechanism that involves modification of COX2 to produce a new active enzyme; not merely blocking the activity of COX2. It does this through acetylation of COX2 yielding a product that is an active 15R-lipoxygenase (31). When arachidonic acid or n-3 PUFA interact with this new lipoxygenase followed by 5-LO actions, the product is a longer acting epimer of lipoxins called aspirin triggered or epi-lipoxins. Statins have a similar property wherein they nitrosylate COX2 yielding a 15R-LO product (31). Intrinsically, cytochrome P450 enzyme complex may also produce 15R-HETE in the absence of a stimulus from aspirin (30–32). SPMs are present in exudates. Resolving exudates are also comprised of n-3 fatty acid derived pro-resolving mediators, including protectins, resolvins and maresins.

Resolvins of the E- and D-series are derived enzymatically from EPA and DHA, respectively, via intrinsic mechanisms whereas, COX-2 and LOX activities acetylated by aspirin also lead to generation of aspirin triggered epimers in a fashion similar to 15-epi-lipoxins (10).

The autacoids produced from EPA via these enzymatic processes are termed E-series resolvins (RvE). Similarly, the derivatives of DHA were termed D-series resolvins (RvD). Another family of chemically active products derived from DHA and characterized by the presence of a conjugated triene double-bond are named protectins. The nomenclature of resolvins was adopted to signify their potent immunoregulatory and anti-inflammatory actions (10). Protectins or neuroprotectins (protectins derived from neural tissues) were named to signify the protective character of 10,17-docosatriene and its anti-inflammatory nature (11, 33). EPA derived compounds such as 18R-HEPA and 18R-HEPE have also been demonstrated to be present in resolving exudates (8). Transcellular synthesis of RvE1 in the vasculature, in the presence of aspirin, resulted in the formation of 18R-HEPE from EPA mediated by endothelial cell derived COX2 and further, leukocyte derived 5-LOX mediated RvE1 formation utilizing 18R-HEPE as the substrate (8, 34). The two major resolvin series derived from DHA include the RvD1-6 and their aspirin triggered isomers (AT-RvD1-6) (35).

17S-hydroperoxy-DHA derived from DHA through an enzymatic reaction mediated by 15-LOX and later by 5-LOX leads to the formation of the D-series of resolvins. In the case of their aspirin triggered epimers, 17R-HpDHA is derived from DHA through a mechanism mediated by COX-2 acetylated by aspirin also subsequently acts as a 5-LOX substrate for an eventual epimeric variant transformation.

Not just resolvins and protectins but maresins are also groups of additional compounds derived from DHA that have been observed in resolving exudates and exhibit pro-resolving and protective activities (11, 12). This is evidenced by the fact that 15-LOX mediated formation of protectin D1 from 17S-HpDHA and 12-LOX mediated maresin 1 (MaR1) formation from 14S-HpDHA have been observed at sites of inflammation (31, 36).

It is essential to understand how significantly the process of resolution differs from that of inhibition. Traditional therapeutic methodologies have focused on anti-inflammatory therapies, which are based on the concept of inhibiting the proinflammatory process. However, in doing so, they also cut-off the signals necessary to initiate and sustain the process of resolution. This is a critical caveat since the process of resolution is central to the favorable outcome of the inflammation cascade, since it reverses the inflammatory process and signals a return to homoeostasis and restoration of cellular structure. While anti-inflammatory strategies act to block enzymes or antagonize relevant receptors, the SPMs exert their activity in an agonistic manner through their interaction with their corresponding receptors. A G-protein coupled receptor, FPR2/ALX binds 15-epi-LXA₄ and LXA₄ with significant affinity. Other receptors for SPMs have also been identified such as GPR32 for LXA₄ chemR23/CMKLR1/ERV1, BLT1 for RvE1, GPR32/DRV1, ALX/FPR2 for RvD1, GPR18/DRV2 for RvD2, GPR32 for RvD3, GPR37 for PD1 and LGR6 for MaR1 (37–39).

There appears to be an overlap amongst some of the receptors in terms of binding compounds from the SPM family. A notable finding has been that of RvD1 exhibiting equipotent activity to LXA₄ upon binding with ALX (37). Further, AT-RvD1, RvD3 and RvD1 all demonstrated high affinity binding to GPR32 (37). The understanding of these pathways is significant since disruption leads to impaired resolution that, in turn, leads an acute inflammatory lesion to progress into a chronic state (27, 40). This disruption in the resolution response may occur as a result of inadequacies in enzyme synthesis, receptor expression, essential PUFA deficiency or intra-cellular signaling. Even though the families of these immunoresolvents are structurally distinct, it is their common functional role in the resolution of inflammation that unites them as SPMs. Studies from experimental models have demonstrated these limit damage to tissues, promote healing, control the inflammatory response, decrease the interval to resolution and alleviate pain. These compounds do not act alone but are components of a larger resolution response of the body, which includes cytokines, annexin A1 protein, carbon monoxide and microRNAs and cyclin dependent kinase inhibitors (9, 41–44).

It was over a century ago that Metchnikoff noted that macrophagic clearance of neutrophils tended to resolve inflammation (16). As subsequent research identified the initiators of leukocyte recruitment to sites of insult, the thought process which evolved was to either block these signals or remove the initiators of inflammation in order to prevent inflammation. It was believed that the chemoattractants so involved, gradually undergo dilution and dissipation in a passive manner to end the inflammatory phase. It appears that the fundamental processes surrounding the resolution of inflammation, such as removal of apoptotic PMNs (polymorphonuclear neutrophils) and cessation of tissue-entry of PMNs are impacted by SPMs. This has been demonstrated in studies which have observed in resolving exudates, that cellular interactions expound signals to impair the influx of neutrophils and upregulate macrophagic clearance of these as well, both considered key processes for the resolution of inflammation.

It has been demonstrated that prostaglandins participate in the initial stages of inflammation impacting the production of pro-resolving mediators by stimulating mRNA translation for the responsible enzymes (26). This essentially is a “class-switching” of the lipid mediators to go from ones which are pro-inflammatory to ones which are pro-resolving in action. Temporal analyses of exudates point towards the biosynthesis of lipoxins subsequent to an early appearance of prostaglandins and leukotrienes. The appearance of lipoxins has been correlated with the resolution phase of inflammation (45). Macrophages of the M1-like and M2-like type have been observed to exhibit different responses to stimulation by pathogens and pharmacological inhibitors. The difference lies in the distinction between the lipid mediator profiles that are produced, which further characterizes the pro-resolving and inflammatory cell phenotypes. PGE₂ and LTB₄ are produced by M1-like macrophages and a simultaneous stimulation of the M2-like phenotype as a result of a challenge from S. aureus and E. coli (11, 46). From this, one may appreciate the significance of the lipid mediator class switch, which appears to impact the inflammatory cascade at numerous levels. It has also been observed that an inhibitor of microsomal prostaglandin E₂ synthase-1 and 5-LOX selectively downregulates PG and LT production in the M1-like phenotype but enhances maresin and resolvin production in the M2-like variant (47).

Further credence to the extrinsic mechanism of SPM production can be evidenced by the observation that Resolvin E2, another bioactive member was identified when the common E-series precursor 18-HEPE was subjected to human recombinant 5-LOX (48). In general, SPMs being agonists have the capacity to signal important events in the resolution phase such as stimulating the clearance of apoptotic cells by macrophages and downregulating neutrophil infiltration (15). The pro-resolution and anti-inflammatory processes are not alike. The former involves agonists (SPMs) to halt the influx of neutrophils and stimulate non-phlogistic macrophage responses, these two cardinal features of resolution lead to a restoration of homoeostasis (49).

Every SPM has characteristic proresolving activity that is of significant importance to the resolution of inflammation. These include stopping or limiting neutrophil influx, cytokine/chemokine counter regulation, pain reduction and stimulation of nonphlogistic macrophage activity (50). SPMs act as agonists binding to receptors on multiple targets (neutrophils, macrophages, stromal cells) individually in order to bring about resolution. SPM production in humans is temporal with SPMs acting selectively by signaling resolution to control inflammation without being immunosuppressive (50, 51). In periodontal, kidney, eye and lung diseases, their actions have been demonstrated to be organ protective (50, 51).

SPMs, diurnal variation, and hormonal influence

SPM production demonstrates a diurnal pattern of regulation. A central mechanism requisite for the maintenance of resolution at the tissue level has been elucidated to involve the biosynthesis of pro-resolving mediators by acetylcholine (Ach) release. Ach levels have been demonstrated to be high in the early hours of the day in healthy volunteers. Blood from these volunteers when incubated with Ach demonstrated an upregulation of RvD_n-_{3 DPA} (52). Reduced plasma levels of RvD_n-_{3 DPA} in the early morning hours, essentially a loss of the diurnal regulation mechanism, has been postulated to contribute to the onset and propagation of cardiovascular disease (CVD) (52).

Uncovering the dysregulated circadian rhythmic production of pro-resolving mediators in various disease processes may aid in developing therapeutic strategies, especially in light of studies that have demonstrated the circadian rhythm regulated production of IL-6, TNF-alpha and Ly6c^hi monocytes (53, 54).

The role of hormonal regulation of SPMs has been demonstrated in a selective and rapid upregulation of SPMs characterized by a typical profile including RvD1 and RvD2 observed in mice administered parathyroid hormone (PTH), which triggers a pro-resolving circuit in the backdrop of bone remodeling (55).

Androgen DHT and estrogen have been demonstrated to downregulate the action of the pro-inflammatory LTB₄. Indeed, a sex-based difference has been observed in the reaction of cultured conjunctival goblet cells to LXA₄, with human male cells demonstrating a greater Ca²⁺ response (56). Similarly, in human tear samples, it was found that males demonstrated higher levels of RvD1 and RvD2 (57).

These findings suggest that future studies should further evaluate sex-based differences in SPM production and response also controlling for time of day.

The role of SPMs in infectious diseases

The inflammatory process has time and again been demonstrated to be a key underlying factor in the pathophysiology of numerous infectious disease processes. Naturally, a family of compounds that act to resolve this inflammation would potentially be of immense benefit in not only understanding the disease but in therapeutics as well. Recently, scientific literature has discussed the role SPMs may play in host modulation for several infectious diseases, which provides the scope for exploring a potentially novel therapeutic modality.

Inflammation has a central role to play in pneumonia, a highly prevalent disease of concern both at the community- and hospital acquired-levels. Typically, pneumonia elicits an acute response which is self-limiting in nature. In certain cases, this may progress into acute respiratory distress syndrome (ARDS) which is characterized by respiratory failure and hypoxemia (58). In cases of pneumonia induced by Escherichia coli, Lipoxin A₄ (LXA₄) has been observed to stimulate BCL-2-associated death promoter (BAD) phosphorylation and decrease the expression of myeloid cell leukemia sequence 1 (MCL1), which causes neutrophil apoptosis (58). RvE1 has also been observed to stimulate neutrophil apoptosis but via a different mechanism of activating caspases (58). In both the above situations, the severity associated with lung inflammation in its acute phase is blunted as a result of neutrophil death. Additionally, in a mouse model of pneumonia induced by E. coli, RvE1 has been demonstrated to decrease local pro-inflammatory cytokine production and promote bacterial clearance (59). It was shown that the actions of SPMs aid in E. coli clearance and the decreased levels of host inflammation, which enhanced survival (59). It is quite apparent that resolving the inflammatory process provided the added advantage of microbial clearance, which tends to act as the initiator in a number of disease processes.

Another infectious disease of bacterial etiology (but tick vector), Lyme disease, involves an inflammatory component that manifests after exposure to the initial etiological agent, which microbial in nature. Mouse models of Lyme disease have helped elucidate the systemic and local control of inflammation (60). In mice with an impaired SPM production mechanism, i.e., those deficient in 5-LOX, infection with Borrelia burgdorferi caused a similar pattern of arthritis development as it did in wild type counterparts, the key feature, however, was that the lack of resolvins and lipoxins impaired the ability of the host to resolve arthritis, giving rise to chronic disease, the inflammatory response of which persisted long after the causative agent was cleared (60).

Tuberculosis, in both its typical pulmonary and extra-pulmonary forms, is a disease of concern particularly in the developing world. In a pattern similar to other infectious diseases, it involves both a microbial and inflammatory component. The host response to Mycobacterium tuberculosis involves a balance between pro-inflammatory and pro-resolving mediators, which determines microbial clearance as well as pathogen induced inflammation (61). In a mouse model, it has been demonstrated that infection with Mycobacterium tuberculosis led to an increase in the levels of LTB₄ (pro-inflammatory) and LXA₄ (pro-resolving) with high levels of the latter being maintained during the chronic phase of the infection (61). Further, 5-LOX deficient animals have demonstrated increased survival with M. tuberculosis infections (61). This demonstrates the importance of the inflammatory response in determining disease outcomes. As was discussed previously, it is the inflammatory response which begets the generation of the resolution component. The M. tuberculosis strain has been related to lipoxin generation in the host which points towards SPMs effecting host modulation of the inflammatory response in tuberculosis infections (62). Either LXA₄ or LTB₄, if produced in excess, may result in a skewed response of the host to M. tuberculosis infection, which related to a dysregulation in the expression of tumor necrosis factor (TNF) (62).

Hence, both the pro-resolution and pro-inflammatory pathways seem to be important in determining host defense and outcomes of pathogen caused inflammation (63). It would appear that a therapeutic modality involving antibiotics to clear the pathogen along with SPMs to manage the immune response would be effective. This is further given credence by the finding that varying rates of infection were observed for human variants for the LTA4H and ALOX5 loci, both of which interfere with LXA₄ and LTB₄ production (64, 65).

Perhaps the most serious complication arising from a bacterial infection in its acute phase is that of sepsis. The host response in such cases tends to involve a rapidly progressing system-wide immune dysregulation which may result in shock (66). In a mouse cecal ligation puncture model, treatment of sepsis with LXA₄ downregulated pro-inflammatory cytokine production and reduced gram-negative bacterial numbers, which resulted in improved survival (66, 67). RvD2, by means of downregulating the activity of nuclear factor-κB (NF-κB), regulates pro-inflammatory signals and thereby the overall inflammatory response at the systemic level (50, 59, 66, 67). As was demonstrated in a mouse model of sepsis, administration of RvD2 led to a significant decrease in cytokine production, particularly that of IL-10, IL-6 and interferon-α (IFN-α) (43). There was also reduced infiltration of leukocytes at the infection site (50). It is interesting to note that controlling the inflammatory response in such a manner brings about an overall reduction in bacterial counts both at the systemic and local levels along with an improvement in the overall survival of these animals (50).

Another consideration is one involving the timing of SPM administration. It was demonstrated in a mouse pneumosepsis model that treatment with LXA₄ in the early stages limited the immune response since it reduced leukocyte infiltration. It was also noted that these mice had a deterioration in their survival rate along with impaired bacterial clearance (68). On the contrary, when LXA₄ was utilized in the later stages of treatment, it demonstrated certain positive effects such as satisfactory infection clearance while blunting the protraction of the inflammatory response and thereby improving survival (69). By means of their activity affecting bacterial clearance and downregulation of the pathological inflammatory response, SPMs have been demonstrated to decrease antibiotic dosage requirements for clearing bacterial infections (67, 69). This finding assumes significance in the face of the growing global threat of antibiotic resistance.

SPMs also regulate the mechanisms by which certain viral pathogens interact with the host. In a comparison between influenza strains of varying virulence, it has been observed that the more virulent strains cause greater suppression of lipoxins and hence, an enhanced dissemination of the virus within the host (70). Protectin D1 levels have been observed to be downregulated by highly virulent influenza strains such as H5N1, which reinforces the inverse relationship between SPM activity and strain virulence (71). Apart from modifying the host immune response, protectin D1 and the isomeric protectin DX limit viral replication by scrambling the nuclear export mechanism (11, 45, 46). In fact, protectin D1 has been observed to exhibit better clinical outcomes in cases of influenza virus infections (72). Infected mice, treated with protectin D1 even as late as 48 h into the infection, reported an improvement in survival (72). This finding appears to be important when contemporary antiviral therapies seem to be declining in effectiveness (73). Infection with the respiratory syncytial virus (RSV), another respiratory pathogen of considerable relevance, is characterized by macrophage-driven bronchiolitis which is subsequently resolved by their alternatively activated counterparts (74). This may be explained by the fact that alternatively fated macrophages appear to have a relation to RSV mediated COX-2, RvE1 and LXA₄ related protective action (74, 75).

Herpes Simplex Virus (HSV) infections tend to be particularly distressful and recurrent in their presentation with the potential to progress into states of morbidity. Ocular HSV infection presents a useful model to demonstrate control of the virus at the local level via a strong inflammatory response, the chronicity of which may have significant morbidity. In mice with ocular herpes, it was observed that treatment with topical RvE1 was associated with a reduced number of neutrophils, Th17 and Th1 cells in the cornea (50). The mechanisms for this were hypothesized to be multiple, including a downregulation of CD4⁺ T cells and neutrophil influx, increased anti-inflammatory mediator production and reduced production of pro-inflammatory mediators (76). One study in particular demonstrated that RvE1 may be utilized to regulate severity of lesions in immunopathologies of a viral origin (75). This essentially provides evidence of SPMs regulating the immune response initially elicited by microbial stimulus. The timely involvement of SPMs in the inflammatory cascade is crucial to the outcome of the inflammatory response.

Based on findings from a mouse model it has been suggested that lipoxin induction in response to stimulation by Toxoplasma gondii extract serves as a potent pathway for regulating the function of dendritic cells during the host innate immune response (77). Wild type mice exposed to T. gondii infection produced LXA₄ during the early stages of the chronic infection, whereas mice deficient in 5-Lipooxygenase [5-LO(−/−)] exhibited shorter survival during the same time frame characterized by encephalitis (78). The mortality of these mice was attributable to greater levels of IFN-gamma and IL-12 and was prevented altogether by treatment with a stable analogue of LXA4 (78), again evidencing the essential role played by SPMs in determining the outcome of inflammation. Lipoxins have an alleged protective role in other parasitic infections such as those involving Plasmodium species, Angiostrongylus costaricensis and Trypanosoma cruzi (79–81).

SPMs in periodontal disease

Inflammation and dysbiosis

Inflammation was initially described as possessing certain cardinal signs. These may be considered the result of endogenous and exogenous chemical mediators released as a result of insult. Microbial peptides may act as exogenous mediators which serve as chemoattractants to signal neutrophil infiltration at the site of insult, where these may act by phagocytosing cell debris and microorganisms (107). Phagosomes within neutrophils fuse with lysosomal granules to mature into phagolysosomes that contain enzymes and reactive oxygen species to process the entrapped debris and microorganisms (107). At this stage, the initial inflammatory response can be viewed as one which is protective in nature and its timely resolution would ensure that it is self-limiting as well (107).

A failure of timely resolution of inflammation due to any number of factors would generally mean that the acute inflammatory episode would progress into a more protracted phase of chronic inflammation (108). This is likely to happen in situations where biofilms are involved wherein the microbial community is able to mount a sufficient defense against the host response leading to collateral damage (108). A great deal of theoretical knowledge surrounding the concept of dysbiosis in periodontal disease is based out of experience with research of the gut microbiome. With the complexity of biofilm structure and the potential multitude of host responses it may elicit at various levels, it would not be completely unfair to hypothesize that no one particular microorganism or “keystone” pathogen would be responsible for the initiation of disease. Indeed, there is no such evidence in literature to support such a finding (108). This adds further credence to the role of the inflammatory process in the pathogenesis of periodontal disease. Further, it is recognized that bacteria involved in disease initiation are generally commensal in nature and the so called periodontopathogens form a very minor portion of the biofilm in its early stages (109).

The ecological plaque hypothesis was the first to recognize that dysbiosis of the microbiome would be the result of a persistent and excessive inflammatory response along with pocket formation, which essentially alters the environment in which microorganisms grow by exerting selective pressure upon other specific microorganisms (110). The microbial community pertaining to the periodontium remains generally stable in a state of health while maintaining a dynamic equilibrium (108). Gingivitis may be considered as representative of homoeostasis in that it tends to remain a stable inflammatory lesion (108). It is a failure of timely resolution of inflammation that slides into a chronic phase leading to a loss of tissue (108). Bacteria associated with periodontal disease increase in significant numbers with the progress of the lesion (108). Similarly, a shift to healthy state also involves a change in the composition of the bacterial community (108, 111, 112).

While there is no doubt that polymicrobial insult causes gingivitis, whether the disease progresses is determined by the host response to this insult. This assumes particular importance when one considers the wealth of evidence implicating the host response as the factor responsible for driving tissue destruction (113, 114). Recent literature has suggested that the host immune response may dictate biofilm composition (103). Essentially, this implies that the inflammatory response in turn causes an alteration of the biofilm microenvironment and leads to specific selection of microorganisms. From this, one could infer that inflammation in the periodontal pocket would precede the overgrowth of certain periodontopathogens such as P. gingivalis and Tannerella forsythia at this site (115). Naturally, the initiating factor of disease falls into question. Microbial diversity appears to be stable in both health and severe forms of periodontal disease, whereas it is in shallow pockets that a greater diversity of microorganisms has been observed. A longitudinal study by Tanner et al. demonstrated that there appeared to be no particular microorganisms that preceded the occurrence of attachment loss. They found that gingival inflammation was the only reliable predictor of attachment loss (115).

Accumulating evidence of these concepts over the years has rendered the initial assumption of specific periodontopathogens causing disease as invalid. Coming back full circle to the ecological plaque hypothesis, one may view periodontal disease pathogenesis as the result of plaque accumulation which elicits an inflammatory response that in turn alters the microenvironment of the biofilm, specifically selecting for certain “pathogens” to overgrow, which further magnify the inflammatory response and enter a cyclical process of disease progression. Indeed, it has been demonstrated in a rabbit model that the progression and even onset of P.g induced periodontitis was prevented by Resolvin E1 (RvE1) by greater than 95% (106).

An overview of SPMs, their precursors, target cells and cell-specific activity is provided (Table 1).

Conclusion

In summary, it would appear that SPMs do not act alone via a purely immunological pathway but exert effects on dysbiosis as well. This assumes significant importance in terms of our understanding of periodontal disease, its etiopathology as well as treatment. It would be logical to argue that periodontal disease must be treated as an immunological imbalance created as a result of microbial insult and not just an isolated case of the latter infecting host tissues to cause the disease. This is evidenced quite clearly in the increased diversity and microbial load in periodontal disease when compared to exogenous infections. Clearly, there appears to be immunological factors at play which modify the bacterial diversity and numbers in periodontal disease. With such an understanding, it would be more appropriate to state that Periodontitis is an inflammatory disease initiated by bacteria.

Funding Statement

The author(s) declare financial support was received for the research, authorship, and/or publication of this article.

Supported in part by NIH, NIDCR grants DE025020 and DE032406.

Author contributions

VS: Conceptualization, Data curation, Formal Analysis, Investigation, Methodology, Software, Validation, Visualization, Writing – original draft, Writing – review and editing. TD: Conceptualization, Data curation, Formal Analysis, Funding acquisition, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – review and editing.

Conflict of interest

TD is a named as inventor on Forsyth owned patents that have been licensed for development. He is a founder of Nocendra, Inc., a Forsyth spin out company developing SPMs for treatment of periodontitis.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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