S100A8/A9 promotes renal fibrosis by driving macrophage-to-myofibroblast transition via the TLR4/NF-κB pathway.

Abstract

Renal interstitial fibrosis is a key pathological feature associated with the progression of chronic kidney disease (CKD) progression. Macrophages play a central role in renal inflammation and fibrosis, and the S100 calcium binding protein A8/A9 (S100A8/A9) protein that they express participates in the immune response as an important regulatory inflammatory factor. Therefore, this study aimed to investigate the role of S100A8/A9 in M2-driven macrophage-to-myofibroblast transition (MMT) during progressive fibrosis in patients with CKD. We analyzed renal biopsy tissues from patients with CKD, constructed S100A9 overexpression and macrophage-specific knockdown mouse models, and developed an in vitro transforming growth factor β1 (TGF-β1)-induced MMT cell model. Our results revealed that S100A8/A9 was significantly upregulated in fibrotic kidneys and was mainly expressed in CD68/F4/80macrophages with an MMT phenotype. Further experiments demonstrated that S100A9 knockdown significantly reduced renal interstitial fibrosis, collagen deposition, and tissue damage in mice with unilateral ureteral obstruction (UUO), and inhibited MMT. Conversely, S100A9 overexpression exacerbated the fibrotic phenotype. Moreover, both in vitro and in vivo, knockdown of S100A9 or pharmacological inhibition with the S100A8/A9 inhibitor paquinimod blocked the activation of the toll-like receptor 4 (TLR4)/ myeloid differentiation primary response gene 88 (MyD88)/ nuclear factor kappa-B (NF-κB) signaling pathway, reduced M2 macrophage polarization, and attenuated MMT. These findings suggest that S100A8/A9 may drives M2 macrophage-mediated MMT via the TLR4/NF-κB pathway, thereby promoting renal fibrosis. Therefore, targeting S100A8/A9 may represent a promising approach for the treatment of renal fibrosis in CKD.