Species-specific differences in regulation of macrophage inflammation by the C3a-C3a receptor axis.

Complement is an important arm of the innate immune system. Recent studies have shown that products of complement pathway activation can interact directly with other innate immune signaling molecules, including TLRs and inflammasome family members, during some infectious and chronic inflammatory disorders. Activation of the complement system generates anaphylatoxins, such as C3a and C5a, which modulate inflammation. However, the biological effects of interactions between the anaphylatoxins with their receptors may vary across species. In this study, we demonstrate that human complement and rat complement differ in the way they modulate the inflammatory response to the human pathogen, Neisseria gonorrhoeae, as well as purified pathogen-associated ligands, such as LPS. While rat serum down-regulates MyD88-dependent pro-inflammatory cytokine responses in macrophages, human serum has no effect, or in some cases an enhancing effect. Further, the inhibitory effect of rat serum on otherwise pro-inflammatory stimuli is mediated by complement, specifically C3a-C3a receptor interactions, via an undefined signaling mechanism that down-regulates the transcription factor, NF-κB and NLRP3 inflammasome-mediated caspase-1 activation. This study highlights important functional differences between rodent and human complement that could explain some of the differences in immune responses between these two species. Understanding the crosstalk between complement and other arms of the innate immune system will facilitate the development of better anti-inflammatory therapeutics.