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

Camille Cohen, Rana Mhaidly, Hugo Croizer, Yann Kieffer, Renaud Leclere, Anne Vincent-Salomon, Catherine Robley, Dany Anglicheau, Marion Rabant, Aurélie Sannier, Marc-Olivier Timsit, Sean Eddy, Matthias Kretzler, Wenjun Ju and Fatima Mechta-Grigoriou ()
Additional contact information
Camille Cohen: PSL Research University
Rana Mhaidly: PSL Research University
Hugo Croizer: PSL Research University
Yann Kieffer: PSL Research University
Renaud Leclere: Institut Curie Hospital Group
Anne Vincent-Salomon: Institut Curie Hospital Group
Catherine Robley: PSL Research University
Dany Anglicheau: Paris Cité University, Inserm U1151
Marion Rabant: Paris Cité University
Aurélie Sannier: Paris Cité University, Inserm, U1148
Marc-Olivier Timsit: Paris Cité University
Sean Eddy: University of Michigan
Matthias Kretzler: University of Michigan
Wenjun Ju: University of Michigan
Fatima Mechta-Grigoriou: PSL Research University

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-44886-z

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