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  • br Transparency document br Introduction Inflammation

    2019-07-11


    Transparency document
    Introduction Inflammation is a physiological response of the immune system to defend the body against injury or infection [1,2]. Generally, inflammation is considered as a protective response to injury or infection, due to its functions in eliminating pathogenic stimuli and maintaining homeostasis of the immune system [3]. However, numerous studies have described a “dual role” of inflammation, as excessive inflammation can be potentially harmful to the body because it can cause host damage [4]. Thus, inflammation can be a double-edged sword that needs to be tightly regulated to avoid excessive tissue damage and inflammatory disease. Macrophages, a highly heterogeneous population derived from the myeloid cell lineage, are the key Belinostat (PXD101) during the inflammatory processes [5,6]. In response to stimuli, macrophages are activated and acquire distinct functional abilities; pro-inflammatory M1 (classically activated macrophages) and anti-inflammatory M2 (alternatively activated macrophages). Dysregulation of macrophage polarization has been shown to contribute to aberrant immune responses and inflammatory disease [[7], [8], [9]]. In the early stage of inflammation, macrophages are activated and polarized to an M1 phenotype, which can produce pro-inflammatory cytokines and lead to tissue damage [10]. Therefore, regulatory mechanisms that control the polarization of macrophages during the inflammatory process require further clarification. During the past decade, myeloid-derived suppressor cells (MDSCs) have been recognized as a novel heterogeneous population of immature myeloid cells that play a critical role in both innate and adaptive immunity [11,12]. Under pathological conditions, such as acute and chronic inflammatory diseases, normal differentiation of immature myeloid cells is blocked to form MDSCs [12]. MDSCs act as an immune suppressor via production of high levels of immunosuppressive mediators, including Arginase-1 (Arg-1), inducible nitric oxide synthase (iNOS) and interleukin-10 (IL-10) [12]. In mice, MDSCs can broadly be characterized as CD11b+Gr-1+. More specifically, MDSCs can be delineated into two types: granulocytic MDSCs (G-MDSCs) and monocytic MDSCs (M-MDSCs), which are identified as CD11b+Ly6G+Ly6Clow phenotype and CD11b+Ly6G−Ly6Chigh phenotype, respectively. Notably, we and others have demonstrated that MDSC population are significantly expanded in inflammatory diseases and contribute to control of inappropriate inflammatory activation by inhibiting M1 macrophage polarization [13,14]. Regulation of the expansion and function of MDSCs can significantly affect the activation of immune response and influence the pathogenesis of inflammatory diseases [[15], [16], [17]]. However, the intrinsic regulatory mechanisms of expansion and function of MDSCs in inflammation remains largely unexplored. Thus, it is imperative to clarify the potential regulatory mechanism to enable better control of inflammation. CD180, also known as RP105, is a TLR-like protein that mainly expressed on B lymphocytes, macrophages, and dendritic cells (DCs) [18]. An increasing body of evidence has emerged to show that CD180 can influence the development, homeostasis, and survival of immune cells, including macrophages, DCs, and B lymphocytes [[19], [20], [21]], indicating a complex association between CD180 and inflammation. CD180 enhances the activation of TLR4 signaling pathways in B cells, but functions as an endogenous inhibitor of TLR4 signaling in macrophages and DCs [22]. Furthermore, CD180 has been reported to enhance TLR2-mediated activation of macrophages [23]. These studies suggest that CD180 plays opposing regulatory roles different cells via mechanisms that are not well understood. Thus, in-depth study of the effect of CD180 in inflammatory diseases is compelling. Considering that MDSCs are a heterogeneous population of cells, generally composed of progenitors and precursors of dendritic cells, macrophages, and granulocytes [12], we hypothesized that CD180 is expressed on MDSCs and plays an immune regulatory role on MDSCs. We investigated the expression of CD180 on MDSCs and its role in regulating the accumulation and immunosuppressive activity of MDSCs in endotoxic shock, which is a life-threatening response caused by disordered immune responses to infection. We found that CD180 is robustly expressed by MDSCs and that mice challenged with LPS exhibited increased CD180 expression on MDSCs derived from spleen compared with control cells. Ligation of CD180 by anti-CD180 antibody not only inhibited accumulation of MDSCs by inhibiting phosphorylation of STAT3, but also inhibited the immunosuppressive activity of MDSCs through inhibition of Arg-1 expression. Moreover, in vivo studies showed that ligation of CD180 inhibited the accumulation and immunosuppressive activity of G-MDSCs and attenuated pathological lesions in mice challenged with LPS. Taken together, our studies uncover a significant role of CD180 in regulating the accumulation and functional activity of MDSCs and that CD180 may be a critical pathogenic factor in inflammation.