Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza
Myeloid TBK1 Signaling Contributes to the Immune Response to Influenza
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DOI：
10.1165/rcmb.2018-0122oc
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发表时间：
2019-03-01
影响因子：
6.4
通讯作者：
Doerschuk, Claire M.
中科院分区：
文献类型：
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作者：
Hagan, Robert S.;Torres-Castillo, Jose;Doerschuk, Claire M.
巨噬细胞提供宿主对甲型流感病毒（IAV）感染的应答的关键要素，包括I型IFN和炎性细胞因子和趋化因子的表达。TBK 1（TNF受体相关因子家族成员相关NF-κ B激活物结合激酶1）在某些细胞类型中有助于IFN表达和抗病毒应答，但其在体内对IV的先天应答中的作用尚不清楚。我们假设巨噬细胞TBK 1有助于宿主防御和IAV病理的IFN和非IFN组分。我们产生了骨髓条件性TBK 1基因敲除小鼠，并评估了IAV感染的体外和体内后果。TBK 1的骨髓特异性体内丢失导致宿主对IAV的反应不太严重，如通过相对于野生型小鼠降低的死亡率、体重减轻和缺氧以及BAL液中较少的炎性变化所评估的，尽管病毒载量没有差异。缺乏髓系TBK 1的小鼠表现出较少的CD 64（+）SiglecF（-）Ly 6C（hi）炎性巨噬细胞募集，较少的炎性细胞因子在BAL液中表达，以及较少的IFN调节因子和NF-κ B靶基因在肺中表达。分类的肺泡巨噬细胞，炎性巨噬细胞和肺间质巨噬细胞的分析显示，每个亚群需要TBK 1的不同组成部分的响应IAV感染。我们的研究结果定义了髓系TBK 1在IAV诱导的肺部炎症中的作用，除了IFN I型表达，并指出髓系TBK 1是病毒诱导的肺损伤的中央和细胞类型特异性调节因子。
Macrophages provide key elements of the host response to influenza A virus (IAV) infection, including expression of type I IFN and inflammatory cytokines and chemokines. TBK1 (TNF receptor-associated factor family member-associated NF-kappa B activator-binding kinase 1) contributes to IFN expression and antiviral responses in some cell types, but its role in the innate response to IA V in vivo is unknown. We hypothesized that macrophage TBK1 contributes to both IFN and non-IFN components of host defense and IAV pathology. We generated myeloid-conditional TBK1 knockout mice and assessed the in vitro and in vivo consequences of IAV infection. Myeloid-specific loss of TBK1 in vivo resulted in less severe host response to IAV, as assessed by decreased mortality, weight loss, and hypoxia and less inflammatory changes in BAL fluid relative to wild-type mice despite no differences in viral load. Mice lacking myeloid TBK1 showed less recruitment of CD64(+)SiglecF(-)Ly6C(hi) inflammatory macrophages, less expression of inflammatory cytokines in the BAL fluid, and less expression of both IFN regulatory factor and NF-KB target genes in the lung. Analysis of sorted alveolar macrophages, inflammatory macrophages, and lung interstitial macrophages revealed that each subpopulation requires TBK1 for distinct components of the response to IAV infection. Our findings define roles for myeloid TBK1 in IAV-induced lung inflammation apart from IFN type I expression and point to myeloid TBK1 as a central and cell type-specific regulator of virus-induced lung damage.