Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages
Hematopoietic cell-derived RELMα regulates hookworm immunity through effects on macrophages
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DOI：
10.1002/jlb.4a0917-369rr
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发表时间：
2018-10-01
影响因子：
5.5
通讯作者：
Nair, Meera G.
中科院分区：
文献类型：
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作者：
Batugedara, Hashini M.;Li, Jiang;Nair, Meera G.
抵抗素样分子α（RELMα）是在2型（Th2）细胞因子诱导的炎症（包括蠕虫感染和过敏）中高度分泌的一种蛋白质。在感染巴西日圆线虫（Nb）时，RELMα会抑制Th2炎症反应。RELMα由免疫细胞和上皮细胞（EC）表达；然而，免疫细胞来源的与上皮细胞来源的RELMα的功能影响尚不清楚。我们制备了骨髓（BM）嵌合体，其骨髓细胞或非骨髓细胞中RELMα缺陷（RELMα（-/-）），并用Nb感染它们。非骨髓RELMα（-/-）嵌合体与RELMα（+/+）小鼠具有相似的炎症反应和寄生虫负荷。相比之下，RELMα（-/-）和骨髓RELMα（-/-）小鼠均表现出Nb诱导的肺部和肠道炎症增加，与Th2细胞因子升高和Nb杀伤增加相关。CD11c（+）肺巨噬细胞是骨髓来源的RELMα的主要来源，并且能够介导Nb杀伤。因此，我们采用巨噬细胞 - 蠕虫共培养系统来研究RELMα是否调节巨噬细胞介导的Nb杀伤。与RELMα（+/+）巨噬细胞相比，RELMα（-/-）巨噬细胞与Nb的结合增加，且Nb发育功能受损。补充重组RELMα可部分逆转这种表型。基因表达分析显示，RELMα降低了细胞黏附和Fc受体信号通路，这些通路与巨噬细胞介导的蠕虫杀伤相关。总之，这些研究表明，骨髓来源的RELMα对于抑制Nb免疫反应是必要且充分的，并确定RELMα的一种作用机制是通过抑制巨噬细胞募集以及与Nb的相互作用。我们的研究结果表明，RELMα作为一种免疫制动器，通过限制组织损伤和延迟寄生虫排出，为宿主和寄生虫提供互利的效果。
Resistin-like molecule alpha (RELM alpha) is a highly secreted protein in type 2 (Th2) cytokine-induced inflammation including helminth infection and allergy. In infection with Nippostrongylus brasiliensis (Nb), RELM alpha dampens Th2 inflammatory responses. RELM alpha is expressed by immune cells, and by epithelial cells (EC); however, the functional impact of immune versus EC-derived RELM alpha is unknown. We generated bone marrow (BM) chimeras that were RELM alpha deficient (RELM alpha(-/-)) in BM or non BM cells and infected them with Nb. Non BM RELM alpha(-/-) chimeras had comparable inflammatory responses and parasite burdens to RELM alpha(+/+) mice. In contrast, both RELM alpha(-/-) and BM RELM alpha(-/-) mice exhibited increased Nb-induced lung and intestinal inflammation, correlated with elevated Th2 cytokines and Nb killing. CD11c(+) lung macrophages were the dominant BM-derived source of RELM alpha and can mediate Nb killing. Therefore, we employed a macrophage-worm co-culture system to investigate whether RELM alpha regulates macrophage-mediated Nb killing. Compared to RELM alpha(+/+) macrophages, RELM alpha(-/-) macrophages exhibited increased binding to Nb and functionally impaired Nb development. Supplementation with recombinant RELM alpha partially reversed this phenotype. Gene expression analysis revealed that RELM alpha decreased cell adhesion and Fc receptor signaling pathways, which are associated with macrophage-mediated helminth killing. Collectively, these studies demonstrate that BM-derived RELM alpha is necessary and sufficient to dampen Nb immune responses, and identify that one mechanism of action of RELM alpha is through inhibiting macrophage recruitment and interaction with Nb. Our findings suggest that RELM alpha acts as an immune brake that provides mutually beneficial effects for the host and parasite by limiting tissue damage and delaying parasite expulsion.