Hirsch Ivan, Janovec Vaclav, Stranska Ruzena, Bendriss-Vermare Nathalie
Faculty of Science, Charles University, Prague, Czech Republic.
Institute of Molecular Genetics, ASCR, Prague, Czech Republic.
Front Immunol. 2017 Apr 7;8:394. doi: 10.3389/fimmu.2017.00394. eCollection 2017.
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.
天然免疫细胞通过病原体识别受体（PRR）感知微生物感染和自身配体，这些受体如与基于免疫受体酪氨酸的激活基序（ITAM）相关的Toll样受体（TLR）和调节性受体（RR）。PRR信号传导和反馈抑制机制的快速激活及协同作用必须参与其中，以确保宿主防御功能，并防止与过度激活相关的细胞毒性。与ITAM相关的RR可产生刺激性信号，或者矛盾的是，也可产生抑制性信号。与ITAM相关的RR网络，连同TLR信号通路，负责巨噬细胞和树突状细胞对其微环境的免疫原性或耐受性反应。在巨噬细胞中，ITAM相关受体的低亲和力结合会抑制TLR4信号传导，而ITAM相关受体的高亲和力结合则会导致TLR4信号增强以及对细胞外细胞因子微环境信号的抗性。与巨噬细胞不同，浆细胞样树突状细胞（pDC）中的TLR7/9信号传导会被ITAM相关RR的高亲和力结合所抑制，而低亲和力结合则没有任何影响。令人惊讶的是，在传统树突状细胞中尚未报道ITAM相关受体信号对TLR途径的干扰。在此，我们概述了作用于TLR和ITAM信号通路交叉点的分子机制，并探讨了pDC中ITAM相关受体的高亲和力结合如何抑制TLR7/9信号传导这一问题。细胞背景以及ITAM和TLR信号通路的时空参与导致巨噬细胞与pDC激活产生不同结果。虽然细胞因子和TLR信号传导的交叉调节以及抗原呈递是ITAM相关RR在巨噬细胞中的主要功能，但这些受体在pDC中的主要作用似乎与抑制细胞因子产生以及pDC激活后恢复耐受性状态有关。对TLR和ITAM信号进行药物靶向可能是治疗与pDC相关的慢性感染、癌症以及自身免疫和炎症性疾病的一种有吸引力的新治疗方法。
