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  • br Materials and methods br Results br Discussion MDSCs

    2019-07-11


    Materials and methods
    Results
    Discussion MDSCs were originally identified as a population of cells with immunosuppressive activity in cancer [[26], [27], [28]]. Recent studies show that inflammation has a key role in inducing MDSC development and accumulation, and that MDSCs participate in regulating activation of inflammatory responses [29,30]. There is convincing evidence that many cancers and inflammatory diseases are caused by the inhibition of the immunosuppressive activities of MDSCs. We and others have demonstrated that MDSCs are involved in the early phase of endotoxic shock [13,31]. However, the intrinsic mechanisms of MDSC generation and/or regulation requires further investigation, and understanding these mechanisms will further our understanding of the pathogenesis of inflammatory diseases. CD180, a TLR-like molecule, was originally identified as a 105 kDa protein (RP105) expressed on antigen presenting cells, such as macrophages, myeloid dendritic cells and Tadalafil [18]. MDSCs are immature myeloid progenitors, thus it is reasonable to assume that CD180 might be expressed on MDSCs where it can modulate the accumulation and immunosuppressive activity of MDSCs. In the present study, we have demonstrated that MDSCs from mice challenged with LPS express elevated levels of CD180. Moreover, ligation of CD180 by anti-CD180 antibody significantly inhibited the accumulation and immunosuppressive activity of MDSCs, both in vitro and in vivo. Injection of anti-CD180 antibody attenuated LPS-induced endotoxic shock. These data indicate that CD180 is involved in the pathogenesis of endotoxic shock by regulating the accumulation and immunosuppressive activity of MDSCs. Previously, we and others have demonstrated that demonstrated that Gr-1+CD11b+ MDSCs were accumulated in mice challenged with LPS compared with controls [13,32,33]. We found that the percentage of G-MDSCs was significantly increased, while the percentage of M-MDSCs was reduced in mice challenged with LPS compared with controls. In fact, many studies have found that the changes of the two subsets, M-MDSCs and G-MDSCs, are not synchronized under pathological conditions. For example, MDSCs were significantly accumulated in both the spleen and liver from mice infected with T. congolense and the increased numbers of MDSCs were due mainly to an increase in the numbers of M-MDSC subtype. In contrast, there was a profound reduction in the numbers of G-MDSC subtype [34]. The percentage and absolute numbers of MDSCs in S. japonicum infected mice were higher than that in normal mice. However, the percentage of G-MDSCs increased significantly, while the change of M-MDSCs was not significant [35]. We guess that there may be some factors which can affect the differentiation of M-MDSCs and reduce the proportion of M-MDSCs. However, to date, it is still unknown the specific mechanism that lead to the decrease of MDSCs. It's worth noting that MDSCs are a heterogeneous population of cells that resemble an immature or undifferentiated phenotype. LPS can induce MDSCs from an immature or undifferentiated phenotype to a mature or differentiated phenotype. We guess that the reduction of M-MDSCs maybe related with LPS in mice challenged with LPS. In further studies, we will pay attention to this problem and try to explore the mechanism. Numerous studies have shown that MDSCs participate in the pathogenesis of other diseases, including pathogen infection, autoimmune diseases, and cancer [11]. Since CD180 can regulate the accumulation and immunosuppressive function of MDSCs in endotoxic shock, we anticipate that CD180 may also participate in the pathogenesis of other diseases involving MDSCs via the same mechanisms. It is worth exploring the role of CD180 in the pathogenesis of these diseases. We have previously shown that ligation of CD180 on B cells inhibits activation of IFN-α signaling by inhibiting tyrosine phosphorylation of STAT2 [25]. This suggested that CD180 may negatively regulate activation of the JAK-STAT signaling pathway. Consistent with this, the results presented here show that ligation of CD180 significantly inhibits the expansion of MDSCs induced by GM-CSF plus IL-6 via inhibition of STAT3 phosphorylation. Indeed, further investigations are required to clarify the mechanisms of CD180-mediated inhibition of STAT3 phosphorylation.