Fractalkine–CX3CR1-dependent recruitment and retention of human CD1c+ myeloid dendritic cells by in vitro–activated proximal tubular epithelial cells

Andrew J. Kassianos, Xiangju Wang, Sandeep Sampangi, Sadia Afrin, Ray Wilkinson, Helen Healy

Chemokines play pivotal roles in tissue recruitment and retention of leukocytes, with CX3CR1 recently identified as a chemokine receptor that selectively targets mouse kidney dendritic cells (DCs). We have previously demonstrated increased tubulointerstitial recruitment of human transforming growth factor-β (TGF-β)-producing DCs in renal fibrosis and chronic kidney disease (CKD). However, little is known about the mechanism of human DC recruitment and retention within the renal interstitium. We identified CD1c(+) DCs as the predominant source of profibrotic TGF-β and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c(+) DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon-γ and tumor necrosis factor-α induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c(+) DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c(+) DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF-β-producing CD1c(+) DCs are recruited and retained in the renal tubulointerstitium by PTEC-derived fractalkine. These cells are then positioned to play a role in the development of fibrosis and progression of chronic kidney disease.Kidney International advance online publication, 14 January 2015; doi:10.1038/ki.2014.407.