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

Abstract

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.

Transcriptional Classification and Functional Characterization of Human Airway Macrophage and Dendritic Cell Subsets

“…As an example, the chemokine receptor, CX3CR1 , which was uniquely upregulated by the DC clade (Fig. 6D), is also highly expressed by resident renal BDCA1 + DC (87). Overall, Langerin + , BDCA1 + CD14 + , and BDCA1 + CD14 − DC are the “true DC” of the human airways that can be separated transcriptionally from AM, CD14 + BDCA1 − DC, and CD14 − BDCA1 − DC of the MΦ clade.…”

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression

“…23 Both CXCR3 and CX3CR1 have been implicated in human tubulointerstitial injury and loss of kidney function. 36,37 It is thus tempting to speculate that these chemokine receptors are pivotal in NK cell recruitment and retention in human CKD.…”

“…26 The proinflammatory roles of IFN-g in kidney disease include the following: (i) M1 macrophage activation, 39 (ii) modulation of effector T-cell responses, 40 (iii) induction of major histocompatibility complex class I and II molecules for antigen presentation, 41 and (iv) upregulation of chemokines that augment immune cell infiltration. 37 In addition to its proinflammatory effects, IFN-g has also been reported to limit kidney disease progression and preserve renal function. [42][43][44] These studies highlight the complex nature of IFN-g dependent on the context of the kidney disease process.…”

The Tubulointerstitial Pathophysiology of Progressive Kidney Disease

“…With injury, macrophages are recruited through the production of inflammatory cytokines such as MCP-1 67 and fractalkine 68 to remove debris and permit regeneration. 69 Interrupting adhesion molecule expression decreases this recruitment.…”