Bone Marrow-Derived Macrophage NLRP3 Mediates Renal Fibrosis by triggering TGF-β/Smad3-mediated Macrophage-Myofibroblast Transition.

NLRP3 is a well-recognized pro-inflammatory mediator in renal inflammation. Here, we report a new role for NLRP3 in the pathogenesis of renal fibrosis. Using a large-scale single-cell RNA sequencing, we found that NLRP3 is mainly expressed by macrophages, but not by tubular cells. Functionally, we unexpectedly found that NLRP3 is profibrotic, as mice lacking NLRP3 or macrophage-specific deletion of NLRP3 were protected from UUO and ischemia reperfusion injury (IRI)-induced renal fibrosis. Mechanistically, we uncovered that NLRP3 directly bound TGF-β receptors II and I to trigger the activation of TGF-β/Smad3 signaling and progressive renal fibrosis via the macrophage-myofibroblast transition (MMT) process. This was further confirmed by pharmacological inhibition in a mouse model of UUO in which blockade of NLRP3 inhibited TGF-β/Smad3 signaling, MMT, and progressive renal fibrosis. In conclusion, macrophage NLRP3 is profibrotic and mediates renal fibrosis via the TGF-β/Smad3-MMT mechanism. Targeting macrophage NLRP3 may be a promising therapeutic approach for CKD.