Targeting the MDSC-Th17 axis: Sinomenine suppresses rheumatoid arthritis by disrupting arginase-1-mediated immune crosstalk.

Myeloid-derived suppressor cells (MDSC) play a critical role in rheumatoid arthritis (RA) pathogenesis by promoting Th17 cell polarization toward a pro-inflammatory and pro-osteoclastogenic phenotype. Sinomenine (SIN) is an effective anti-inflammatory and anti-osteoclastogenic drug for RA treatment. It remains unclear whether SIN could modulate MDSC mediated Th17 differentiation. Here we report that SIN significantly alleviated Collagen-induced arthritis (CIA) and suppressed Th17 responses in vivo. Strikingly, SIN blocked the MDSC-enhanced Th17 response, as evidenced by the loss of IL-17 A and RANKL production in Th17 cells induced by SIN-conditioned MDSC. Mechanistically, SIN bound to JAK1, inhibiting IL-6-induced activation of the JAK1/STAT3 pathway and suppressing MDSC expression of arginase-1 (Arg1), which acts as a crucial mediator of MDSC-driven Th17 responses. Additionally, SIN inhibited RANKL-induced osteoclastogenesis from MDSC. Selective depletion of MDSC abolished therapeutic efficacy of SIN in vivo, whereas adoptive transfer of SIN-preconditioned MDSC abolished their pro-arthritic activity. Our study demonstrates that SIN alleviates RA by reprogramming pathogenic MDSC to disrupt the MDSC-Th17 crosstalk through dual inhibition of JAK1/STAT3/Arg1 pathway and RANKL-driven osteoclastogenesis.