Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI

Abstract

Background: Activation of the type 1 interleukin 1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of acute kidney injury (AKI). IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. Methods: To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid (AA) exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. Results: Single-cell RNA sequencing analyses demonstrated robust IL-1 expression in myeloid cell populations and low level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death via local suppression of apolipoprotein M (Apom). In contrast, IL-1R1 activation in endothelial cells ameliorated AA-induced AKI by restoring VEGFA-dependent endothelial cell viability and density. Conclusions: These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI following toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.

Targeting IL-1 Receptor Signaling in AKI

“…This study is significant because the authors demonstrate for the first time using a PTEC-specific or endothelial-specific IL-1R1 deletion mouse model that IL-1/IL-1R1 signaling in PTECs and endothelial cells has opposed functional effects in toxininduced AKI. 10 The authors show that deletion of IL-1R1 in PTECs improved kidney function in mice after aristolochic acid and cisplatin induced AKI by diminishing tubular injury without affecting the intrarenal expression of proinflammatory mediators. 10 Thus, IL-1R1 signaling in PTECs may not directly facilitate tubular injury through enhancing the inflammatory response but rather indirectly by mediating cell injury and apoptosis in part using fatty acid oxidation and lipid metabolism in PTECs.…”

“…10 The authors show that deletion of IL-1R1 in PTECs improved kidney function in mice after aristolochic acid and cisplatin induced AKI by diminishing tubular injury without affecting the intrarenal expression of proinflammatory mediators. 10 Thus, IL-1R1 signaling in PTECs may not directly facilitate tubular injury through enhancing the inflammatory response but rather indirectly by mediating cell injury and apoptosis in part using fatty acid oxidation and lipid metabolism in PTECs. 10 Mechanistically, IL-1R1 activation in PTECs suppresses apolipoprotein M and sphingosine-1-phosphate signaling to reprogram the cellular metabolism in toxininduced AKI.…”

“…The article by Ren et al in this issue of JASN aims to dissect the pathomechanisms through which IL-1R1 signaling in kidney cell lineages affects on the outcomes of toxin-induced AKI in mice. 10 Single-cell RNA sequencing analysis revealed a greater expression of IL-1/IL-1R1 genes and downstream signaling pathways in proximal tubular epithelial cells (PTECs) and the kidney endothelium after aristolochic acid exposure as compared with infiltrating immune cells. 10 This led the authors to hypothesize that IL-1/IL-1R1 signaling in PTECs and endothelial cells may contribute to the inflammatory response in toxin-induced AKI.…”

“…Knowing the complexity of cell interactions and the differential function of IL-1R1 signaling in kidney cell lineages during AKI in rodents, 10,11 a critical question arises how and to what extent, if any, the results in rodents can be translated into humans to improve the clinical outcomes in patients with AKI. One therapeutic approach could be cell-mediated drug delivery targeting systems to specifically target IL-1R1 signaling and downstream signaling events to limit necroinflammation.…”

“…10 Thus, IL-1R1 signaling in PTECs may not directly facilitate tubular injury through enhancing the inflammatory response but rather indirectly by mediating cell injury and apoptosis in part using fatty acid oxidation and lipid metabolism in PTECs. 10 Mechanistically, IL-1R1 activation in PTECs suppresses apolipoprotein M and sphingosine-1-phosphate signaling to reprogram the cellular metabolism in toxininduced AKI. 10 In contrast to the deleterious effects of tubular IL-1R1, the authors show that IL-1R1 activation in endothelial cells diminishes aristol/ochic acid-induced AKI by augmenting the local expression of the proangiogenesis vascular endothelial growth factor A and thereby preserving endothelial cell density and viability.…”