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

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- beta (TGF- beta )-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 super(+) DCs as the predominant source of profibrotic TGF- beta and highest expressors of the fractalkine receptor CX3CR1 within the renal DC compartment. Immunohistochemical analysis of diseased human kidney biopsies showed colocalization of CD1c super(+) DCs with fractalkine-positive proximal tubular epithelial cells (PTECs). Human primary PTEC activation with interferon- gamma and tumor necrosis factor- alpha induced both secreted and surface fractalkine expression. In line with this, we found fractalkine-dependent chemotaxis of CD1c super(+) DCs to supernatant from activated PTECs. Finally, in comparison with unactivated PTECs, we showed significantly increased adhesion of CD1c super(+) DCs to activated PTECs via a fractalkine-dependent mechanism. Thus, TGF- beta -producing CD1c super(+) 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.