Macrophages (M?) play a critical role in innate immunity at mucosal surfaces (e.g. periodontium), responding to microbial challenge and producing elevated levels of various cytokines that contribute to host innate defenses. Recent evidence demonstrated an important role for the plasticity of M? phenotypes, not only in the resulting function of these cells in various tissues, but also delineated clear differences in the stimulatory signals that result in M1 and M2 M? cells. P. gingivalis has been routinely described as a primary member of the pathogenic biofilms of periodontitis lesions. However, gaps exist in our knowledge of how host M?s interact with P. gingivalis infection derived from the subgingival sulci of the oral cavity. More importantly, how pathogens like P. gingivalis generate M1 inflammatory macrophages during this disease has not been elucidated. This R15 proposal expands on our recent findings of the capacity of P. gingivalis to alter the functional characteristics of M? to create a hyperinflammatory environment in the gingival tissues and, as such, affect the characteristics of the microbial ecology (e.g. dysbiosis). Additionally, this effect on M? would undermine normal M1 to M2 tissue changes that would hinder resolution of the chronic inflammatory tissue damage. The overall Hypothesis is that infection of M? with P. gingivalis results in a functional phenotype (M1pg) that would impact the inflammatory cytokine milieu in the tissues. Additionally, a crucial aspect of resolving inflammation and wound healing is the ability of M1 macrophages to transition to M2 macrophages in the tissues. We propose that the M1pg is modified by this infection to abrogate transition to an M2 cell and impede a return to homeostasis.
Specific Aim 1 : To determine the role of STAT and SOCS responses as a molecular basis of M1pg macrophage polarization induced by P. gingivalis.
This aim will emphasize characterizing macrophage polarization following interaction with P. gingivalis as a primary periodontopathogen.
The aim will focus on the ability of this opportunistic pathogen to affect intracellular signaling pathways, particularly STAT1 and SOCS1/3 as regulators of TLR elicited NF?B functions resulting in M1pg phenotype and contributing to a dysfunctional host-bacterial interaction at infected sites.
Specific Aim 2 : To determine the ability of P. gingivalis to prevent conversion of M1pg into M2 immunoregulatory, healing macrophages or drive M2 cells to an M1 inflammatory macrophage. Since M2 cells are critical for the transition of an inflammatory lesion to a wound healing environment, the capacity of Pg to interfere with natural M1-M2 polarization processes could be a portion of its armamentarium eliciting chronic inflammation and tissue destruction.
This aim will investigate the ability of P. gingivalis to inhibit inflammatory resolution via blocking of M1-M2 macrophage transitions. The impact of successfully testing the hypotheses proposed in this application will provide seminal data on the effect of P. gingivalis causing unrestrained biologic processes of ?periodontitis activating? M? within the complex oral microbial environment, and exacerbation of chronic inflammation.
Macrophages are crucial for linking innate immunity to adaptive immune responses in mucosal tissues. While these cells exist in the periodontium, there are limited data that characterize how macrophages respond to the complex oral microbial ecology. Completion of the proposed studies will significantly advance our understanding of the capacity of P. gingivalis, a crucial oral pathogen, to enhance chronic inflammatory tissue destruction and subvert tissue healing process through its effects on the polarization of macrophages in periodontal tissues.
