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KMID : 0578320200430030251
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Molecules and Cells
2020 Volume.43 No. 3 p.251 ~ p.263
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Flagellin-Stimulated Production of Interferon-β Promotes Anti-Flagellin IgG2c and IgA Responses
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Kang Won-Dae
Park A-Reum
Huh Ji-Won
You Gi-Hoon
Jung Da-Jung
Song Man-Ki
Lee Heung-Kyu
Kim You-Me
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Abstract
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Flagellin, a major structural protein of the flagellum found in all motile bacteria, activates the TLR5- or NLRC4 inflammasome-dependent signaling pathway to induce innate immune responses. Flagellin can also serve as a specific antigen for the adaptive immune system and stimulate anti-flagellin antibody responses. Failure to recognize commensal-derived flagellin in TLR5-deficient mice leads to the reduction in anti-flagellin IgA antibodies at steady state and causes microbial dysbiosis and mucosal barrier breach by flagellated bacteria to promote chronic intestinal inflammation. Despite the important role of anti-flagellin antibodies in maintaining the intestinal homeostasis, regulatory mechanisms underlying the flagellin-specific antibody responses are not well understood. In this study, we show that flagellin induces interferon-β (IFN-β) production and subsequently activates type I IFN receptor signaling in a TLR5- and MyD88-dependent manner in vitro and in vivo . Internalization of TLR5 from the plasma membrane to the acidic environment of endolysosomes was required for the production of IFN-β, but not for other proinflammatory cytokines. In addition, we found that antiflagellin IgG2c and IgA responses were severely impaired in interferon-alpha receptor 1 (IFNAR1)-deficient mice, suggesting that IFN-β produced by the flagellin stimulation regulates anti-flagellin antibody class switching. Our findings shed a new light on the regulation of flagellin-mediated immune activation and may help find new strategies to promote the intestinal health and develop mucosal vaccines.
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KEYWORD
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anti-flagellin antibody, flagellin, IgA, interferon-β, Toll-like receptor 5
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