Differential capacity for complement receptor‐mediated immune evasion by Porphyromonas gingivalis depending on the type of innate leukocyte

Abstract

The complement system plays a central role in immunity and inflammation, although certain pathogens can exploit complement to undermine protective immunity. In this context, the periodontal keystone pathogen Porphyromonas gingivalis (Pg) was previously shown by our group to evade killing by neutrophils or macrophages through exploitation of complement C5a receptor 1 (C5aR1) and complement receptor-3 (CR3). Here, we examined whether Pg uses complement receptors to also subvert killing by dendritic cells. In line with earlier independent studies, intracellular viable Pg bacteria could be recovered from mouse bone marrow-derived dendritic cells (BMDC) or human monocyte-derived dendritic cells (MDDC) exposed to the pathogen. However, in the presence of C5a, the intracellular survival of Pg was significantly decreased in a C5aR1-dependent way. Further work using wild-type and receptor-knockout BMDC showed that, in the presence of C3a, the C3a receptor (C3aR) similarly enhanced the intracellular killing of Pg. In contrast, C5aR2, an alternative receptor for C5a (G protein-coupled receptor 77), was associated with increased intracellular Pg viable counts, consistent with the notion that C5aR2 functions as a negative regulator of C5aR1 activity. Moreover, Pg failed to utilize CR3 as a phagocytic receptor in BMDCs, in contrast to our earlier findings in macrophages where CR3-mediated uptake promotes Pg survival. Collectively, these data show that complement receptors mediate cell-type-specific effects on how innate leukocytes handle Pg, which appears to exploit complement to preferentially evade those cells (neutrophils and macrophages) that are most often encountered in its predominant niche, the periodontal pocket.

More than complementing Tolls: complement–Toll‐like receptor synergy and crosstalk in innate immunity and inflammation

“…Thus, it can be reasoned that dendritic cells and macrophages express distinct isoforms of adenylate cyclase, thus C3aR‐ or C5aR‐induced Gαi signaling has different effects on the regulation of the enzyme isoforms. Another cell type‐specific difference is that whereas C5a inhibits P. gingivalis ‐induced IL‐12p70 in macrophages, C5a promotes P. gingivalis ‐induced IL‐12p70 in dendritic cells . The C5a‐induced inhibition of IL‐12p70 by P. gingivalis is mediated by ERK1/2 signaling, consistent with an earlier report that C5a‐induced ERK1/2 signaling inhibits enterobacterial LPS‐induced IL‐12p70 in macrophages .…”

“…Another cell type-specific difference is that whereas C5a inhibits P. gingivalis-induced IL-12p70 in macrophages, 27 C5a promotes P. gingivalis-induced IL-12p70 in dendritic cells. 90 The C5a-induced inhibition of IL-12p70 by P. gingivalis is mediated by ERK1/2 signaling, 27 consistent with an earlier report that C5a-induced ERK1/2 signaling inhibits enterobacterial LPS-induced IL-12p70 in macrophages. 69 Whereas C5a induces ERK1/2 signaling also in dendritic cells, 94 the ERK1/2 pathway in this cell type upregulates, rather than inhibits, IL-12p70 production.…”

“…89 Although P. gingivalis can exploit C5aR1 in neutrophils and macrophages to suppress their antimicrobial functions, 19,68 as well as bind CR3 for a safe entry into macrophages, 81 the same receptors on dendritic cells do not seem to enhance the intracellular persistence of P. gingivalis. 90 In stark contrast, C5aR1 promotes the intracellular killing of P. gingivalis in dendritic cells, whereas CR3 does not function as a phagocytic receptor for P. gingivalis. Similar to C5aR1, C3aR enhances the intracellular killing of P. gingivalis in dendritic cells.…”

“…95 Despite its ability to transactivate and bind CR3 in macrophages, P. gingivalis fails to utilize CR3 as a phagocytic receptor in dendritic cells. 90 The reason for this difference is not understood, although a study has suggested that CR3 cannot be readily transactivated in dendritic cells. 96 Therefore, C3aR, C5aR1, and CR3, mediate cell type-specific effects on how innate leukocytes handle P. gingivalis.…”

Immunologic environment influences macrophage response to Porphyromonas gingivalis

“…Periodontal diseases are chronic inflammatory diseases of the periodontium that in severe cases lead to destruction of the hard and soft tissues supporting the teeth, and bacteria-elicited inflammation serves as the nidus of this destructive host response. Porphyromonas gingivalis is an organism associated with chronic periodontitis in part through its ability to stimulate microbial dysbiosis in subgingival plaque, and locally modulate expression of host immune factors (Darveau et al, 2012;Hajishengallis et al, 2015Hajishengallis et al, , 2016. Individuals with periodontal disease present with a complex array of expressed inflammatory and anti-inflammatory mediators (Gemmell et al, 2001a;Seymour & Gemmell, 2001), as well as a complex cellular infiltration with early neutrophilic responses followed by lymphocytes, dendritic cells, and monocytes/macrophages (Charon et al, 1981;Kinane, 2000;Pihlstrom et al, 2005;Schenkein, 2006).…”