Ccr7-dependent Amelioration of Renal Tubular Injury Protects Against Infection-Induced Acute Kidney Injury

Abstract Systemic candidiasis (SC) is a leading cause of nosocomial bloodstream infections, with mortality of >40% despite therapy. In a mouse model of SC, the most highly infected organ is the kidney, and myeloid cells, including dendritic cells (DCs), are integral for host defense. We hypothesized that Ccr7, which mediates DC trafficking and survival, is critical for host defense during SC. Ccr7 and its ligands, Ccl19 and Ccl21, were highly up-regulated in the Candida-infected kidney. All Ccr7−/− mice rapidly succumbed during SC, whereas WT mice had 80% survival at day 14. Infected Ccr7−/− mice had significantly greater kidney fungal burden, with greater tissue damage, and more severe renal failure. Infection in Ccl19−/− mice and in plt/plt mice (that lack Ccl19 and the CCL21a isoform of Ccl21) did not phenocopy the susceptibility of Ccr7−/− mice, indicating that the CCL21b-Ccr7 axis is critical for protection. Surprisingly, bone marrow chimeras revealed that the protective effects of Ccr7 are solely mediated by non-hematopoietic cells. Studies using FACS, IHC, and mRNA from sorted renal cells showed that Ccr7 is expressed by renal tubular cells (RTCs), not other renal stromal cells. Our preliminary data show the Ccr7 is a survival factor for RTCs; indeed, Ccr7 deficiency resulted in significantly greater tubulitis and tubular necrosis during SC. The renal protective effects of Ccr7 were also evident during bacterial sepsis, indicating that Ccr7 is broadly protective against infection-induced acute kidney injury. In summary, our data are the first to implicate Ccr7 in innate control of any pathogen and to uncover the contribution of Ccr7 on non-hematopoietic cells in protection against acute kidney injury and systemic fungal infection.