{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T09:32:03Z","timestamp":1786699923972,"version":"build-2736575974"},"reference-count":123,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Interleukin-33 (IL-33) has long been categorized as a prototypical alarmin released upon cellular injury to initiate Th2-skewed immune responses. However, accumulating evidence from diverse kidney disease models and patient cohorts has unveiled a far more complex and contextually governed functionality. This review synthesizes recent advances to reframe the understanding of IL-33, positioning it not merely as a passive danger signal, but as an active and versatile rheostat of renal pathophysiology. The net effect of IL-33\/ST2 signaling, whether tissue-protective or pro-inflammatory and fibrotic, is critically dictated by the disease microenvironment, encompassing the nature of the initial insult (e.g., ischemia\u2013reperfusion, nephrotoxic agents, or autoimmune complexes), the phase of disease (acute versus chronic), and the local immune\u2013parenchymal cell network. We delineate how the IL-33\/ST2 axis differentially orchestrates key immune effectors, including group 2 innate lymphoid cells (ILC2s), macrophage polarization states, and T cell subsets with particular emphasis on regulatory T cells (Tregs). These interactions in turn shape divergent clinical outcomes, ranging from effective tissue repair and functional recovery to relentless inflammation and progressive fibrosis. By integrating findings across acute kidney injury, diabetic nephropathy, lupus nephritis, and IgA nephropathy, this review underscores the dual, context-dependent nature of IL-33 signaling. We further discuss its emerging potential as a stratified biomarker and a modifiable therapeutic target, and advocate for future strategies that precisely calibrate IL-33\/ST2 activity according to specific pathological contexts, with the goal of achieving optimized and durable renal outcomes.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1887953","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T08:49:00Z","timestamp":1786697340000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond the alarm: unveiling the multifaceted role of IL-33 in kidney disease"],"prefix":"10.3389","volume":"17","author":[{"given":"Mei","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Laboratory Medicine, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suning","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingli","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shengjing Hospital of China Medical University","place":["Shenyang, Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaosong","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Shengjing Hospital of China Medical 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