Myeloid-derived suppressor cells have a proinflammatory role in the pathogenesis of autoimmune arthritis

Abstract

Objectives Although myeloid-derived suppressive cells (MDSCs) have been linked to T-cell tolerance, their role in autoimmune rheumatoid arthritis (RA) remains elusive. Here we investigate the potential association of MDSCs with the disease pathogenesis using a preclinical model of RA and specimen collected from RA patients. Methods The frequency of MDSCs in blood, lymphoid tissues, inflamed paws, or synovial fluid and their association with disease severity, tissue inflammation, and the levels of pathogenic T-helper (Th) 17 cells was examined in arthritic mice or in patients with RA (n=35) and osteoarthritis (OA, n=15). The MDSCs in arthritic mice were also characterized for their phenotype, inflammation status, T-cell suppressive activity, and their capacity of pro-Th17 cell differentiation. The involvement of MDSCs in the disease pathology and a Th17 response was examined by adoptive transfer or antibody depletion of MDSCs in arthritic mice or by co-culturing mouse or human MDSCs with naïve CD4+ T cells under Th17-polarizing conditions. Results MDSCs significantly expanded in arthritic mice and in RA patients, which correlated positively with disease severity and an inflammatory Th17 response. While displaying T-cell suppressive activity, MDSCs from arthritic mice produced high levels of inflammatory cytokines (e.g., IL-1β, TNF-α). Both mouse and human MDSCs promoted Th17 cell polarization ex vivo. Transfer of MDSCs facilitated disease progression, whereas their elimination in arthritic mice ameliorates disease symptoms concomitant with reduction of IL-17A/Th17 cells. Conclusions Our studies suggest that proinflammatory MDSCs with their capacity to drive Th17 cell differentiation may be a critical pathogenic factor in autoimmune arthritis.

Interleukin-10 produced by myeloid-derived suppressor cells is critical for the induction of tregs and attenuation of rheumatoid inflammation in mice

“…Tregs can suppress autoimmune process and maintain peripheral tolerance 24 . A recent paper by Guo et al showed that MDSCs obtained from CIA mice promoted Th17 differentiation in a IL-1 dependent manner and therefore have a proinflammaotory role in the pathogenesis of inflammatory arthritis 19 , which is different from our results. Such discrepancy in the results about the role of MDSCs in various effector CD4+ T cell populations might be due to the context-dependent interaction between MDSCs and different subsets of CD4+ T cells.…”

“…Given the potent immuoregulatory activity of MDSCs, it could be expected that MDSCs could have therapeutic impact on RA. There have been discordant results regarding the effect of MDSCs on RA [12][13][14][15][16][17][18][19] . However, all the previous papers performed adoptive transfer of MDSCs in animal model of RA to verify whether the MDSCs had therapeutic effects on RA.…”

“…However, a few recent papers have shown that MDSCs can aggravate inflammatory arthritis in mice [17][18][19] . Thus, the precise impact of MDSCs on RA remains still unclear.…”

17β-estradiol contributes to the accumulation of myeloid-derived suppressor cells in blood by promoting TNF-α secretion

“…Strikingly, female patients with SLE showed a higher frequency of MDSCs in PBMCs than male patients. Although transplantation of MDSCs can improve the condition of several autoimmune diseases in animal models, several recently published studies have shown that MDSCs play a proinflammatory role in the pathogenesis of EAE and RA by promoting T helper 17 cell differentiation [29][30][31]. Notably, CD11b + Gr-1 + MDSCs are a complex mixture of myeloid phenotypes.…”

“…The protective role of MDSCs against inflammation and autoimmunity has been widely observed in various pathophysiological conditions [26][27][28]. However, several recent studies have shown that MDSCs play a proinflammatory role in the pathogenesis of experimental allergic encephalitis (EAE) and rheumatoid arthritis (RA) by promoting Th17 cells differentiation [29][30][31], suggesting that the roles of MDSCs in inflammatory and autoimmune diseases remain controversial.…”