M1/M2-macrophage phenotypes regulate renal calcium oxalate crystal development

Abstract

In our previous report, M2-macrophage (MΦs) deficient mice showed increased renal calcium oxalate (CaOx) crystal formation; however, the role of MΦs-related-cytokines and chemokines that affect kidney stone formation remains unknown. Here, we investigated the role of M1/M2s in crystal development by using in vitro and in vivo approaches. The crystal phagocytic rate of bone marrow-derived M2MΦs was higher than that of bone marrow-derived MΦs and M1MΦs and increased on co-culture with renal tubular cells (RTCs). However, the amount of crystal attachment on RTCs reduced on co-culture with M2M Φs. In six hyperoxaluric C57BL/6J mice, M1MΦ transfusion and induction by LPS and IFNλ facilitated renal crystal formation, whereas M2MΦ transfusion and induction by IL-4 and IL-13 suppressed renal crystal formation compared with the control. These M2MΦ treatments reduced the expression of crystal-related genes, such as osteopontin and CD44, whereas M1MΦ treatment increased the expression of pro-inflammatory and adhesion-related genes such as IL-6, inducible NOS, TNF-α, C3, and VCAM-1. The expression of M2MΦ-related genes was lower whereas that of M1MΦ-related genes was higher in papillary tissue of CaOx stone formers. Overall, our results suggest that renal crystal development is facilitated by M1MΦs, but suppressed by M2MΦs.