IL-17 mediates neutrophil infiltration and renal fibrosis following recovery from ischemia reperfusion: compensatory role of natural killer cells in athymic rats

Abstract

T cells have been implicated in the pathogenesis of acute kidney injury (AKI) and its progression to chronic kidney disease (CKD). Previous studies suggest that Th17 cells participate during the AKI-to-CKD transition, and inhibition of T cell activity by mycophenolate mofetil (MMF) or losartan attenuates the development of fibrosis following AKI. We hypothesized that T cell-deficient rats may have reduced levels of IL-17 cytokine leading to decreased fibrosis following AKI. Renal ischemis-reperfusion (I/R) was performed on T cell-deficient athymic rats (Foxn1) and control euthymic rats (Foxn1), and CKD progression was hastened by unilateral nephrectomy at and subsequent exposure to 4.0% sodium diet. Renal fibrosis developed in euthymic rats and was reduced by MMF treatment. Athymic rats exhibited a similar degree of fibrosis, but this was unaffected by MMF treatment. FACS analysis demonstrated that the number of IL-17 cells was similar between postischemic athymic vs. euthymic rats. The source of IL-17 production in euthymic rats was predominately from conventional T cells (CD3/CD161). In the absence of conventional T cells in athymic rats, a compensatory pathway involving natural killer cells (CD3/CD161) was the primary source of IL-17. Blockade of IL-17 activity using IL-17Rc receptor significantly decreased fibrosis and neutrophil recruitment in both euthymic and athymic rats compared with vehicle-treated controls. Taken together, these data suggest that IL-17 secretion participates in the pathogenesis of AKI-induced fibrosis possibly via the recruitment of neutrophils and that the source of IL-17 may be from either conventional T cells or NK cells.

Calcium channel Orai1 promotes lymphocyte IL-17 expression and progressive kidney injury

“…Following recovery from I/R injury in rats, subsequent exposure to high-salt diet was shown to hasten the development of interstitial fibrosis, inflammation, proteinuria, and hypertension. These parameters of CKD progression were significantly attenuated by immunosuppression with mycopheno-late (8,9), suggesting that lymphocyte activity also modulates the AKI-to-CKD transition.…”

ETA receptor activation contributes to T cell accumulation in the kidney following ischemia-reperfusion injury

“…IL‐17 has been shown to promote fibrosis and infiltration of immune cells in renal IR injury (Mehrotra et al. ), and has been implicated in alterations in tubular sodium handling and the development of hypertension in response to chronic angiotensin II infusion (Madhur et al. ; Norlander et al.…”

“…Natural Killer cells were also recently identified as a potential source of IL‐17 in post‐IR kidneys (Mehrotra et al. ), and potential nonimmune sources of IL‐17 may include renal epithelial cells (Norlander et al. ).…”

“…IL-17 has been shown to promote fibrosis and infiltration of immune cells in renal IR injury (Mehrotra et al 2017), and has been implicated in alterations in tubular sodium handling and the development of hypertension in response to chronic angiotensin II infusion (Madhur et al 2010;Norlander et al 2016), making it an attractive target in terms of understanding the mechanisms involved in the development of hypertension post-AKI and the increased risk of progression to CKD. However, no significant difference in IL-17a expression was detected between groups in the present study, which was somewhat surprising given several lines of evidence suggesting that ET-1 can stimulate IL-17 production by Th17 or possibly other cell types.…”

“…Interestingly, Cornelius et al (2013) demonstrated that IL-17 infusion had an inhibitory effect on ET-1 production in renal cortex of pregnant female rats but no effect on human umbilical vein endothelial cell ET-1 production, suggesting a complex relationship between the two substances. Natural Killer cells were also recently identified as a potential source of IL-17 in post-IR kidneys (Mehrotra et al 2017), and potential nonimmune sources of IL-17 may include renal epithelial cells (Norlander et al 2016). Accordingly, it remains possible that any effect of ET A receptor blockade to reduce T cell production of IL-17 in the current study was masked by IL-17 production by other cell types.…”