Study On Human FcγRⅡA Induced Training Effect On Mice Macrophages And The Contribution Of These Macrophages On Pathogenicity Of Rheumatoid Arthritis In Mice

Trained immunity is a new concept of the innate immunity proposed recently.This concept points out that innate immune cells can become hyperresponsive after stimulation with PAMP.It means that innate immune cells can protect body from re-infection of pathogens through secreting larger amount of cytokines.It has been proved that trained immunity could be related to the anti-infection or anti-tumor processes.In our previous studies,we have showed that immune complexes(IC)can also induce training effect on human monocytes.In many patients with autoimmune diseases,including rheumatoid arthritis(RA),systemic lupus erythematosus(SLE)and autoimmune vasculitis,etc,autoantibodies and ICs are enriched in blood or deposite in synovial membranes,kidneys,and vascular walls.IC purified from serum of RA patients can also sensitization monocytes to PAMPs via human special Fc?RIIa.RNA-seq analysis of IC primed monocyte showed similar gene profile with synovial macrophages isolated from RA patient.It suggested that IC-primed monocytes have a correlation with pathological injury of RA.In order to find out the contribution of training effect of IC on pathogenesis of RA,my study will try to prove it in vivo using mouse models.Since FcγRⅡA is only expressed on the surface of human innate immune cells,IC induced training effect should be shown in h FcγRⅡA transgenic mice.After injected soluble IC which made up of LTF and LTF monoclonal antibody M860 intraperitoneally,h FcγRⅡA-Tg mice secreted higher concentration pro-inflammatory factors(TNF-?)than WT mice after challenge with LPS in vivo.Accordingly,macrophages isolated from LTF-IC primed h FcγRⅡA-Tg mice was more sensitive to LPS stimulation in vitro.When bone marrow cells of h FcγRⅡA-Tg mice were primed by IC during differentiation to macrophages,the cells were significantly more sensitive to LPS(release of TNF-?)than that of WT mice.Mice were injected intradermally at the base of the tail with collagen type II.h FcγRⅡA-Tg mice showed much more sensitive to collage induced arthritis(CIA)than WT mice.Futhermore,cytokines and chemokines expression of synoid macrophages were compared between h FcγRⅡA-Tg and WT mice.h FcγRⅡA-Tg mice macrophages in CIA model expressed more cytokines and chemokines than that of WT mice,similar to IC primed macrophages in vitro.IC primed macrophages from h FcγRⅡA-Tg mice injected into mouse joints cause arthritis sympothm,including synovial hyperplasia,bone damage,and inflammatory cell infiltration.In conclusion,training activity of IC on macrophages was important for pathogenensis of RA.Th17 is an important pathogenic effect cells in pathogenensis of RA.IC primed human monocyte can promote Th17 cells differentiation in vitro.Th17 differentiation and migration was enhanced in FcγRⅡA-Tg CIA mice as well.OPN is one of the RA-related protein upregulated in IC primed monocyte.Th17 diffferentiation was blocked with anti-OPN in the presence of IC primed monocyte.The concentration of OPN in serum of h FcγRⅡA-Tg CIA mice was also higher than WT mice,indicating the role of OPN in arthritis induced by IC primed macrophages.My research showed IC primed macrophage could induce RA directly for the first time.The mechanism research supplied a new standpoint for pathogenesis of RA and new ideas for the prevention and treatment of RA.