IL-33/ST2 axis mediates hyperplasia of intrarenal urothelium in obstructive renal injury

Abstract

The monolayered intrarenal urothelium covers the renal papilla and ureteropelvic junction (UPJ). In response to increased renal pressure during obstruction or ischemic injuries, intrarenal urothelial cells begin to proliferate and form a multilayered urothelium. Little is known regarding the mechanism and pathophysiological role of urothelium hyperplasia during renal obstruction. In this study, we investigated the expression of interleukin (IL)-33, an IL-1 family cytokine, in kidneys with unilateral ureteral obstruction (UUO)-induced obstructive injury. IL-33 levels in hydronephrotic urine and serum were upregulated 2 days after UUO. The number of ST2-expressing immune cells was increased in the UUO kidney. We found that IL-33 was upregulated in vimentin-positive cells in the cortical and medullar layers and the UPJ stroma. Moreover, IL-33 expression was predominantly induced in multilayered keratin 5-positive urothelial cells in the UPJ. IL-33 was not detected in terminally differentiated superficial umbrella cells expressing uroplakin 3a. In vivo, we confirmed that deficiency of IL33 or its receptor ST2 attenuated UUO-induced hyperplasia of the UPJ urothelium. Deficiency of IL33 attenuated the expression of UUO-induced type 2 inflammatory cytokines and upregulated uroplakins and urothelial differentiation signaling in UPJ tissues. Our results collectively suggest that the IL-33/ST2 axis mediates the activation of innate immune responses and contributes to urothelial hyperplasia by regulating urothelial differentiation in obstructive kidney injury.

Emerging Roles of Interleukin-33-responsive Kidney Group 2 Innate Lymphoid Cells in Acute Kidney Injury

“…Li et al reported that exogenous IL-33 promotes kidney fibrosis via the effector function of AAMs in the UUO model [55]. Our previous study investigated the ST2+ immune cell profile in the kidney, which revealed that the myeloid cells are the major targets of IL-33 in the UUO-induced obstructed kidney [58]. However, the deletion of Il33 reduced the protein levels of type 2 cytokines in the urine isolated from the UUO kidney [58].…”

“…In addition to kidney ILC2s, other ST2-expressing immune populations were also identified. Among the ST2+ cells, the CD45-non-leukocytes, neutrophils, macrophages, T/ILCs, and monocytes comprised 34.8%, 22.3%, 23.1%, 16.2%, and 3.6%, respectively [58]. Compared with the nonobstructed kidneys, the UUO kidneys exhibited a 30-fold increase in the number and a 4.6-fold increase in the percentage of ST2+ neutrophils [58].…”

“…Our previous study investigated the ST2+ immune cell profile in the kidney, which revealed that the myeloid cells are the major targets of IL-33 in the UUO-induced obstructed kidney [58]. However, the deletion of Il33 reduced the protein levels of type 2 cytokines in the urine isolated from the UUO kidney [58]. This suggested that the endogenous IL-33 contributes to the production of the type 2 cytokines in the UUO model.…”

“…Our previous study had analyzed the ST2+ immune cell profile in the unilateral urinary obstruction (UUO) mouse model [58]. The study reported that kidney ILC2s (CD45+Lin-Thy1.2+GATA3+) constitute the major population (approximately 70%) among the total ILC subsets in the normal and injured kidneys [58]. In addition to kidney ILC2s, other ST2-expressing immune populations were also identified.…”

“…Among the ST2+ cells, the CD45-non-leukocytes, neutrophils, macrophages, T/ILCs, and monocytes comprised 34.8%, 22.3%, 23.1%, 16.2%, and 3.6%, respectively [58]. Compared with the nonobstructed kidneys, the UUO kidneys exhibited a 30-fold increase in the number and a 4.6-fold increase in the percentage of ST2+ neutrophils [58]. These results indicate that there is increased infiltration and expansion of ST2+ innate immune cells in the kidney following obstructive injury.…”