Complement Receptor 3 Influences Toll-like Receptor 7/8-Dependent Inflammation

Abstract

Background: Toll-like receptors (TLR) are key components in autoimmune-mediated pathophysiology. Results: Complement receptor 3 (CR3) suppresses TLR7/8 mediated-inflammation by degrading MyD88. The anti-inflammatory function of CR3 is negated if TLR7/8 ligation occurs prior to CR3 activation or in macrophages expressing a genetic variant of CD11b. Conclusion: Environmental and genetic factors influence CR3 signaling. Significance: CR3-specific agonists may be applicable for preventing pathologic TLR7/8 signaling.

Microglial complement receptor 3 regulates brain Aβ levels through secreted proteolytic activity

“…To date, little is known about the effects of CR3 deficiency or LA-1 treatment in microglia relating to the secretory or expression profiles. There is evidence from studies in human PBMC-derived macrophages, human monocyte cell lines (Reed et al, 2013), and in human NK cells (Roberts et al, 2016) that LA-1 treatment can affect key transcription factors, e.g., MyD88, to modulate secretion of cytokines. LA-1 might act as a partial antagonist, reducing signaling that inhibits the secretion of Aβ-degrading enzymes, although leaving other functions unaffected or even enhancing them (e.g., adhesion).…”

A novel pathway of rapid TLR-triggered activation of integrin-dependent leukocyte adhesion that requires Rap1 GTPase

“…(2010 ) proposed that TLR4 ligation induced CD11b activation, which in turn inhibited TLRs by promoting degradation of MyD88 and TRIF, suggesting a negative feedback loop. In addition, engagement of Mac-1 in human monocytes and macrophages was shown to down-regulate TLR7/8-dependent inflammatory responses ( Reed et al. , 2013 ), whereas it negatively regulated immune responses in TLR9-triggered dendritic cells ( Bai et al.…”

Immune-mediated pathology in Duchenne muscular dystrophy

“…Although C3 was localized to all necrotic fibers in DMD, usually well above background levels, the receptor for C3 has been found to negatively regulate TLR7-mediated signaling (by degrading MyD88). Thus, C3 may be serving an anti-inflammatory role in this setting (16). Therefore, it is puzzling that ablation of C3 in mdx mice failed to have an effect on muscle pathology.…”