WNT-dependent interaction between inflammatory fibroblasts and FOLR2+ macrophages promotes fibrosis in chronic kidney disease

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Cohen, Camille | Mhaidly, Rana | Croizer, Hugo | Kieffer, Yann | Leclere, Renaud | Vincent-Salomon, Anne | Robley, Catherine | Anglicheau, Dany | Rabant, Marion | Sannier, Aurélie | Timsit, Marc-Olivier | Eddy, Sean | Kretzler, Matthias | Ju, Wenjun | Mechta-Grigoriou, Fatima

Edité par CCSD ; Nature Publishing Group -

International audience. Chronic kidney disease (CKD) is a public health problem driven by myofibroblast accumulation, leading to interstitial fibrosis. Heterogeneity is a recently recognized characteristic in kidney fibroblasts in CKD, but the role of different populations is still unclear. Here, we characterize a proinflammatory fibroblast population (named CXCL-iFibro), which corresponds to an early state of myofibroblast differentiation in CKD. We demonstrate that CXCL-iFibro co-localize with macrophages in the kidney and participate in their attraction, accumulation, and switch into FOLR2+ macrophages from early CKD stages on. In vitro, macrophages promote the switch of CXCL-iFibro into ECM-secreting myofibroblasts through a WNT/β-catenin-dependent pathway, thereby suggesting a reciprocal crosstalk between these populations of fibroblasts and macrophages. Finally, the detection of CXCL-iFibro at early stages of CKD is predictive of poor patient prognosis, which shows that the CXCL-iFibro population is an early player in CKD progression and demonstrates the clinical relevance of our findings.

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