Anti-Flagellin antibodies dampen TLR5 and NLRC4 innate immune responses to flagellin

Abstract

Abstract The host immune system is constantly exposed to diverse microbial ligands, including flagellin (FliC; a ligand for TLR5 and NLRC4) and lipopolysaccharide (LPS; a ligand for TLR4), whose ability to induce immune tolerance to subsequent exposure is well-documented in vitro. In this study, we investigated the extent to which FliC and LPS could induce immune cross-tolerance to one another in vivo, as well as the interaction between the innate and adaptive immune response to FliC. Mice pre-treated with LPS displayed attenuated serum keratinocyte-derived chemokine [KC; alias interleukin (IL)-8] and IL-6 response to FliC; however, the administration of FliC followed by LPS instead resulted in an additive response. LPS also augmented the serum IL-18 response to FliC; the increment was more pronounced when LPS was administered before, than after, FliC. Intriguingly, the generation of anti-FliC antibodies was notably impaired in mice sequentially challenged with LPS and FliC, compared to mice given only FliC. A strong negative correlation between high anti-FliC titer and reduced KC, IL-6 and IL-18 responses to FliC re-challenge was observed in these mice, suggesting that adaptive immunity could tolerize TLR5 and NLRC4. Indeed, the serum from WT mice with high anti-FliC titer, but not Rag1KO mice, was able to dampen FliC-induced secretion of IL-8 from the human epithelial cell line HT-29. These observations may be relevant in the context of bacterial infection, as we demonstrated that anti-FliC response are protective against systemic infection by Salmonella typhimurium. Taken together, our study delineates a distinct co-operative and reciprocal interaction between the innate and adaptive arms of immunity in modulating their responses to FliC.