The Mechanism Of C-reactive Protein In Regulating Th17 Response

C-reactive protein(CRP)is a typical human acute phase protein,which is highly conserved in evolution.So early studies have suggested that CRP's function is mainly involved in innate immune response.However,in recent years,However,in recent years,with the continuous deepening of research on CRP with cardiovascular diseases and autoimmune diseases,it has been found that the function of CRP is not only limited to innate immunity,but also plays an important role in acquired immune response.Experimental autoimmune encephalomyelitis(EAE),an autoimmune disease mediated by Th1 and Th17 cells,is the most widely used animal model of human multiple sclerosis(MS).A large number of studies have shown that CRP can alleviate EAE,but its related pathological mechanism is unclear.Our previous research found that CRP directly suppresses the Th1 response by binding to the receptors of naive T cells,thereby alleviating EAE.However,in vitro studies of CRP and T cells,we did not find a direct effect of CRP on Th17 response.In particular,after more studies have confirmed the ability of CRP to reverse EAE,whether CRP can participate in Th17 response is particularly important.Thus,we conducted a study on the comprehensive effects of CRP on TH17 response.First,we start with the EAE animal model.By detecting the changes in the response of CRP to various Th cell subtypes in the spleen cells of mice at the peak of EAE disease,we found that CRP inhibited Th17 response in mice as well as Th1 response.In combination with our previous findings,CRP cannot directly regulate Th17 response,so we speculated that CRP regulation of Th17 response was indirectly mediated by Antigen-presenting cell(APC).To test this hypothesis,we simulated the direct and indirect effects of CRP ON Th17 in vitro by co-incubating erythrocyte-lysed splenocytes and CD4+ T cells with CRP,respectively.The results found that CRP can indirectly reduce the response of Th17 with the help of APC,while CRP can regulate the response of Th1 indirectly and directly.In order to examine which APC mediates CRP's regulation of Th17 response.We analyzed the changes of immune cell composition in blood and CNS in EAE mice and found that in addition to T cell infiltration,there were a large number of monocytesderived dendritic cells(mo DCs)infiltration in the CNS during EAE.Therefore,we sorted PBMCs from WT mice and induced them to mo DCs.Then we co-cultured mo DCs with sorted CD4+ T cells and found that CRP can suppress Th17 cell response through mo DCs.Since CRP could not change the infiltration degree of immune cells in CNS,we speculated that CRP indirectly regulated Th17 response by altering the antigen presentation ability of mo DCs.After that,we screened the effect of CRP on the expression of molecules related to antigen presentation ability on the surface of mo DCs by q PCR,and then verified them at the protein level by flow cytometry.Finally,it was confirmed that CRP attenuated the antigen presentation ability of CNS infiltratory mo DCs by inhibiting the expression of MHC-II and CD86.At the same time,we verified our conclusions with the help of CRP-/-mice.The Fc?R2B is the only one has been reported to mediate CRP function in EAE,which is also clearly expressed on DC,so we speculated that CRP may act on mo DCs through Fc?R2B receptor,and then indirectly participate in Th17 response.To this end,we performed the same experiments using Fc?R2B /-mice as in WT mice.The results showed that the suppressive effect of CRP on Th17 response disappeared after the Fc?R2B receptor was knocked out,indicating that it was indeed the Fc?R2B receptor mediated the regulation of CRP on Th17 response.Finally,we tested the NF-?B and ERK signaling pathways related to the activation and survival of DCs.It was found that during the activation of mo DCs,CRP could significantly reduce the expression of NF-?B and p-ERK1/2.In conclusion,through the research in this article,we have concluded that CRP can act on the NF-?B and ERK signaling pathways through the Fc?R2B receptor,thereby reducing the expression of MHC-? and CD86 on mo DCs,reducing the antigen presentation ability of mo DCs,and thus indirectly inhibiting Th17 response.This indirect regulation mechanism of APC enriches our understanding of CRP regulating T cells and alleviating EAE,and also provides new ideas and research directions for the prevention and treatment of MS and other T cell-mediated autoimmune diseases.