Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells.
Cross Talk between Inhibitory Immunoreceptor Tyrosine-Based Activation Motif-Signaling and Toll-Like Receptor Pathways in Macrophages and Dendritic Cells.
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DOI：
10.3389/fimmu.2017.00394
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发表时间：
2017
影响因子：
7.3
通讯作者：
Bendriss-Vermare N
中科院分区：
文献类型：
--
作者：
Hirsch I;Janovec V;Stranska R;Bendriss-Vermare N
先天性免疫细胞通过与基于免疫受体酪氨酸的激活基序（ITAM）相关的病原体识别受体（PRR），如toll样受体（TLR）和调节受体（RR）来感知微生物感染和自身配体。PRRs信号传导和反馈抑制机制的快速激活和协同作用必须参与以确保宿主防御功能并防止与过度激活相关的细胞毒性。ITAM相关的RR可以产生刺激性信号，或者矛盾的是，产生抑制性信号。ITAM相关RR网络与TLR信号通路一起负责巨噬细胞和树突状细胞对其微环境的免疫原性或致耐受性应答。在巨噬细胞中，TLR 4信号传导被ITAM相关受体的低亲合力连接抑制，而ITAM相关受体的高亲合力连接导致TLR 4信号传导的增强以及对细胞外细胞因子微环境信号的抗性。与巨噬细胞相反，浆细胞样DC（pDC）中的TLR 7/9信号传导被ITAM相关RR的高亲合力连接抑制，而低亲合力连接不显示任何作用。令人惊讶的是，ITAM相关受体信号传导与TLR途径的干扰在常规树突状细胞中尚未报道。在这里，我们提出了一个概述的分子机制，在TLR和ITAM信号通路的十字路口，并解决如何在pDC中的ITAM相关受体的高亲和力参与抑制TLR 7/9信号转导的问题。细胞环境和ITAM-和TLR-信号传导途径的时空参与负责巨噬细胞与pDC活化的不同结果。虽然细胞因子和TLR信号传导的交叉调节以及抗原呈递是巨噬细胞中ITAM相关RR的主要功能，但这些受体在pDC中的主要作用似乎与抑制细胞因子产生和在pDC活化后重建致耐受性状态有关。TLR和ITAM信号传导的药理学靶向可能是用于治疗与pDC相关的慢性感染、癌症以及自身免疫性和炎性疾病的有吸引力的新治疗方法。
The innate immune cells sense microbial infection and self-ligands by pathogen recognition receptors (PRRs), such as toll-like receptors (TLRs) and regulatory receptors (RRs), associated with immunoreceptor tyrosine-based activation motif (ITAM). Rapid activation and concerted action of PRRs signaling and feedback inhibitory mechanisms must be engaged to ensure the host defense functions and to prevent cytotoxicity associated with excessive activation. ITAM-associated RRs can generate stimulatory or, paradoxically, inhibitory signals. The network of ITAM-associated RR, together with TLR-signaling pathways, are responsible for immunogenic or tolerogenic responses of macrophages and dendritic cells to their microenvironment. In macrophages, TLR4 signaling is inhibited by low-avidity ligation of ITAM-associated receptors, while high-avidity ligation of ITAM-associated receptors results in potentiation of TLR4 signaling together with resistance to extracellular cytokine microenvironment signals. In contrast to macrophages, TLR7/9 signaling in plasmacytoid DCs (pDCs) is inhibited by high-avidity ligation of ITAM-associated RR, while low-avidity ligation does not show any effect. Surprisingly, interference of ITAM-associated receptor signaling with TLR pathways has not been reported in conventional dendritic cells. Here, we present an overview of molecular mechanisms acting at the crossroads of TLR and ITAM-signaling pathways and address the question of how the high-avidity engagement of the ITAM-associated receptors in pDCs inhibits TLR7/9 signaling. Cellular context and spatiotemporal engagement of ITAM- and TLR-signaling pathways are responsible for different outcomes of macrophage versus pDC activation. While the cross-regulation of cytokine and TLR signaling, together with antigen presentation, are the principal functions of ITAM-associated RR in macrophages, the major role of these receptors in pDCs seems to be related to inhibition of cytokine production and reestablishment of a tolerogenic state following pDC activation. Pharmacologic targeting of TLR and ITAM signaling could be an attractive new therapeutic approach for treatment of chronic infections, cancer, and autoimmune and inflammatory diseases related to pDCs.