Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Abstract

Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.

Honokiol suppresses the aberrant interactions between renal resident macrophages and tubular epithelial cells in lupus nephritis through the NLRP3/IL-33/ST2 axis

“…It induces immune-cell maturation and cytokine release and is involved in the initiation, maintenance, and regression of inflammation, as well as in the physiology and pathology of many diseases [ 29 ]. As an important subtype of ST2, ST2L is highly expressed in the kidney, lungs, and stomach [ 30 ]. A large amount of evidence suggests that ST2L is a functional component of IL-33 signaling, promoting inflammatory responses by activating pro-inflammatory factors, such as NF-κB [ 31 ].…”

Quercetin Ameliorates Renal Injury and Pyroptosis in Lupus Nephritis through Inhibiting IL-33/ST2 Pathway In Vitro and In Vivo

“…Recent studies provide evidence that tubular epithelial cells may contribute to renal fibrogenesis through partial epithelial–mesenchymal transition [ 42 ]. IL-33 is not only a fundamental cytokine in inflammatory diseases but also a profibrotic protein [ 43 ]. In a previous study, IL-33 could induce EMT in HK-2 cells by promoting fibronectin expression [ 44 ].…”

“…The canonical pathway elicited by IL-33 results in stimulation of a receptor complex composed of ST2L and interleukin 1 receptor accessory protein (IL-1RAP) [ 43 ], which triggers the recruitment of MyD88, IRAK1, IRAK4, and TRAF6, followed by activation of downstream signaling pathways, such as NF-κB, c-Jun N-terminal kinase (JNK), p38, and ERK [ 53 ]. A previous study in STZ-induced diabetic rats found that quercetin intervention downregulated the expression of NF-κB in the kidney [ 54 ].…”

Molecular Mechanisms of Cellular Injury and Role of Toxic Heavy Metals in Chronic Kidney Disease

“…The decelerated progression of CKD by sodium-glucose co-transporter 2 (SGLT2) channel inhibitors may be partly from attenuated CD36 expression from downregulated PPAR-γ [ 94 ]. IL-33 may be an important driver of progressive CKD [ 95 ]. IL-33 is a member of the IL-1 cytokine family and exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways.…”

“…IL-33 is a member of the IL-1 cytokine family and exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Recent studies have shown that a sustained activation of the IL-33/ST2 pathway promotes the development of renal fibrosis [ 95 ]. This pathway is a potential target for therapeutic intervention.…”