---
title: "IL-33 and kidney disease: article metadata and reporting gaps in Frontiers in Immunology"
id: "frontiers-in-immunology-13-beyond-the-alarm-unveiling-the-multifaceted-role-of-il-33-in-kidney-disease"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-13-beyond-the-alarm-unveiling-the-multifaceted-role-of-il-33-in-kidney-disease"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887953"
published_at: "2026-08-14T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# IL-33 and kidney disease: article metadata and reporting gaps in Frontiers in Immunology
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-13-beyond-the-alarm-unveiling-the-multifaceted-role-of-il-33-in-kidney-disease
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1887953)
- **Published At:** 2026-08-14T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source provided is a Frontiers in Immunology article page titled “Beyond the alarm: unveiling the multifaceted role of **IL-33** in **kidney disease**.” - The available source content contains site navigation, journal sections, and submission links but does not include the article text, abstract, results, methods, or conclusions. - No experimental data, clinical findings, mechanistic descriptions, patient populations, or therapeutic implications are reported in the provided source content. - Specifics such as study design, sample size, key outcomes, measured biomarkers, or author and institutional information were not present in the copy supplied. - Because the article body and scientific details were not included in the source, this rewrite summarizes only the metadata available and explicitly identifies missing information and reporting gaps. - Readers and clinicians should consult the full article on the journal website for substantive content about **IL-33** biology, its roles in renal pathology, and any clinical or translational implications that the authors reported.
## Clinical Analysis & Structured Key Points
Frontiers | Beyond the alarm: unveiling the multifaceted role of IL-33 in kidney disease REVIEW article Front. Immunol. , 14 August 2026 Sec. Cytokines and Soluble Mediators in Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1887953 Published in Frontiers in Immunology Cytokines and Soluble Mediators in Immunity 7 impact factor 11.3 citescore Editor & Reviewers Edited by A M Athanasia Mouzaki Reviewed by M B Maria Battistone R S Rahul Sharma Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Figure 4 View in article Table 1 Mechanisms underlying IL-33 function. View in article REVIEW article Front. Immunol. , 14 August 2026 Sec. Cytokines and Soluble Mediators in Immunity Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1887953 Beyond the alarm: unveiling the multifaceted role of IL-33 in kidney disease M Y Mei Yang 1 † S M Suning Miao 1 † M Y Mingli Yu 2 † X F Xiaoqing Fu 1 X Q Xiaosong Qin 1 * 1. Department of Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China 2. Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China Article metrics View details Abstract 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–reperfusion, nephrotoxic agents, or autoimmune complexes), the phase of disease (acute versus chronic), and the local immune–parenchymal 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. 1 Introduction Kidney diseases represent a public health challenge on a global scale, with acute kidney injury (AKI) and chronic kidney disease (CKD) emerging as priority areas for prevention and control due to their high incidence, poor prognosis, and substantial healthcare burden ( 1 – 3 ). AKI is defined as a clinical condition marked by a swift reduction in kidney function, caused by multiple factors ( 4 ). Severe cases of AKI may progress to CKD or even result in irreversible renal failure ( 4 , 5 ). According to the underlying pathological mechanisms, CKD is categorized into primary glomerular diseases and secondary kidney diseases. Primary glomerular diseases are the predominant cause of glomerulopathy ( 6 ), with idiopathic membranous nephropathy (IMN) being the most prevalent primary nephropathy, followed by IgA nephropathy ( 6 – 9 ). Among secondary nephropathies, diabetic nephropathy is the most prevalent, succeeded by lupus nephritis ( 6 ). In the context of renal injury and repair, inflammation serves as a critical intermediary ( 10 , 11 ). Beyond infection, several factors contribute to renal inflammation, including ischemia-reperfusion ( 12 ), immune complex formation or deposition ( 13 – 16 ), and the activation of pro-inflammatory pathways ( 17 – 20 ). Notably, primary damage to renal tissue can lead to the generation of cytokines and chemokines, serving as mediators of inflammation ( 10 , 17 ). Recent investigations into the key regulatory factors of renal inflammation and repair have highlighted the IL-33/ST2 signaling axis as a pivotal area of investigation ( 21 ). Interleukin-33 (IL-33), belonging to the IL-1 cytokine superfamily, is abundantly enriched within the nuclei of human epithelial, endothelial, and fibroblast lineages. It is also detectable in the nuclei of various mouse tissues, including epithelial cells, lymphoid organs, brain, and embryonic tissues ( 22 – 24 ). Its role in human diseases is diverse ( 25 ). The receptor for IL-33, known as suppression of tumorigenicity 2 (ST2), is expressed by a wide range of immune cells, including group 2 innate lymphoid cells (ILC2s), Th2 cells, mast cells, eosinophils, basophils, dendritic cells, regulatory T cells (Tregs), NK cells, invariant natural killer T (iNKT) cells, M2-polarized macrophages, and neutrophils ( 26 ). ST2 is present in both a transmembrane form, known as the transmembrane receptor ST2 (ST2L), and a soluble excretory form, referred to as soluble ST2 (sST2) ( 26 , 27 ). Within the nucleus, IL-33 associates with chromatin ( 28 ). Upon tissue damage or necrosis of cells, IL-33 is secreted into the extracellular milieu, where it engages in an autocrine or paracrine fashion by binding to its receptor, ST2 ( 26 , 29 ). This interaction constitutes the IL-33/ST2 signaling pathway, which is vital for modulating a range of pathophysiological processes, including inflammatory responses, angiogenesis, and apoptosis ( 26 , 30 , 31 ). The engagement of IL-33 with its cognate receptor complex, comprised of ST2 and interleukin-1 receptor accessory protein (IL-1RAcP), initiates a cascade of intracellular signaling events. This heterodimeric complex serves as a scaffold for the assembly of key adaptor proteins, notably myeloid differentiation primary response 88 (MyD88), interleukin-1 receptor-associated kinase 1 and 4 (IRAK1/4), as well as tumor necrosis factor receptor-associated factor 6 (TRAF6). The subsequent recruitment of these molecules triggers the activation of the mitogen-activated protein kinase (MAPK) module. In turn, this leads to the stimulation of transcription factors, including nuclear factor kappa B (NF-κB) and activator protein 1 (AP-1), which ultimately upregulate the transcriptional output of genes governing inflammatory responses, cellular viability, and fibrotic processes ( 32 , 33 ). Recent studies have identified an increasingly significant role for IL-33 in kidney diseases. In the context of AKI, IL-33 predominantly exhibits a pro-injury effect, exacerbating renal inflammation and fibrosis, while also contributing to tissue repair. Similarly, in CKD, the IL-33/ST2 signaling pathway demonstrates dual roles, with its protective and pathogenic effects contingent upon the specific type of disease and the duration of signal transduction ( 21 ). By systematically reviewing the current evidence on the IL-33/ST2 axis across different renal pathologies, this article highlights its context-dependent regulatory functions and provides a foundation for better understanding the mechanistic complexity of this pathway in kidney diseases. 2 The role of IL-33 in acute kidney injury The incidence of AKI predominantly affects epithelial cells, endothelial cells, and other parenchymal cells within specific renal regions ( 34 ). Following tissue or cellular damage, an inflammatory response is promptly initiated, mediated by both resident and infiltrating immune cells, including neutrophils and macrophages ( 34 , 35 ). Clinically, AKI is characterized by a high risk of recurrence and prolonged injury duration, with the potential to progress to advanced CKD and end-stage kidney disease (ESKD) ( 36 ). In the context of AKI, the expression of IL-33, a critical regulatory factor in inflammation, is elevated, and its functions are heterogeneous ( 37 – 41 ). To elucidate its mechanism, several AKI models have been established to explore pathogenesis and assess therapeutic strategies ( 42 ), revealing that IL-33 plays diverse roles across different models. The distinct functions of IL-33 in ischemic-reperfusion injury (IRI), cisplatin-, and folic acid-induced AKI are summarized in Figure 1 . Figure 1 Role of IL-33 in acute kidney injury. IL-33 exerts a dual regulatory role in three distinct models of AKI: IRI, cisplatin nephrotoxicity, and folic acid-induced AKI. During the early stage of IRI, IL-33 activates iNKT cells to secrete IFN-γ and IL-17A, which mediate neutrophil recruitment and reactive oxygen species (ROS) burst, aggravating tubular injury. In contrast, during the late stage, IL-33 acts on ILC2s and ST2 + Tregs to induce M2 macrophage polarization and the secretion of anti-inflammatory factors and amphiregulin, thereby promoting renal tubular regeneration and inflammation resolution. In cisplatin-induced AKI, IL-33 upregulates the chemokine CXCL1 via CD4 + T lymphocytes, mediating neutrophil infiltration and exacerbating renal injury. In folic acid-induced AKI, ferroptosis of renal tubular epithelial cells releases IL-33, which in turn promotes Treg expansion and modulates M1/M2 macrophage polarization, initiating local immune responses. 2.1 Model of ischemia-reperfusion injury In the context of IRI, IL-33 has been demonstrated to encourage the expansion of ILC2s, M2 macrophages, and Tregs, thereby initiating Th2 immune responses and concurrently suppressing the production of proinflammatory factors, which collectively confer a protective effect on renal tissues ( 38 ). Furthermore, numerous studies have identified a pro-fibrotic role of IL-33 in the pathophysiology of IRI ( 43 , 44 ). These findings suggest that, beyond its reparative role in acute kidney injury models, IL-33 also contributes to kidney disease pathogenesis. Following IRI-induced damage, IL-33 levels increase in the kidney, facilitating the accumulation of fibroblasts from bone marrow, the generation of myofibroblasts, as well as the recruitment of macrophages and T cells, ultimately leading to renal injury and fibrosis ( 45 ). In the initial stages of IRI, IL-33 directly impacts renal tubular epithelial cells, causing renal tubular necrosis and impaired renal function ( 29 ). As the disease progresses, IL-33, under the synergistic influence of IL-12, can recognize the ST2 receptor on the surface of iNKT cells. This engagement promotes the mobilization and stimulation of iNKT cells, prompting them to secrete interferon-gamma (IFN-γ) and IL-17A, which subsequently act on neutrophils. This process enhances the recruitment of neutrophils to the kidney, thereby exacerbating IRI ( 29 , 46 ). The regulation of IL-33 expression involves complex epigenetic mechanisms. The chromatin remodeling protein brahma-related gene-1 (BRG1) has been shown to mediate IL-33 expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner, involving histone-modifying proteins such as p300, ASH2, and KDM3A, thereby promoting renal injury and fibrosis induced by IRI ( 43 ). However, it is important to note that BRG1 is a broad regulator of the inflammatory response; it also promotes the transcription of other proinflammatory cytokines, including TNF-α, IFN-γ, and MCP-1, in the kidney following ischemic injury ( 47 ). Therefore, the protective effects observed upon BRG1 deletion are likely attributable to the suppression of a panel of proinflammatory mediators, rather than solely the downregulation of IL-33.The IL-33/ST2 axis also plays a critical role in modulating the function of Tregs during renal IRI. Emerging evidence indicates that ST2 expression on Tregs is essential for their immunosuppressive and tissue-reparative functions ( 48 ). Treg-specific deletion of ST2 has been shown to exacerbate kidney injury, inflammation, and fibrosis in murine models of IRI, underscoring the protective role of the ST2 + Treg subset in the resolution of renal injury ( 48 , 49 ). Mechanistically, ST2 + Tregs are enriched for the expression of reparative factors, including amphiregulin (AREG), which contributes to the preservation of tubular epithelial cell viability and the suppression of fibrogenesis ( 50 ). Collectively, these findings highlight the dual nature of the IL-33/ST2 axis, which can both promote and resolve renal IRI depending on the cellular context and the stage of injury. 2.2 Models induced by cisplatin and folic acid In the cisplatin-induced AKI model, the role of IL-33 is context-dependent. In an acute, high-dose model, IL-33 facilitates the production of the chemokine CXCL1 by CD4 + T cells via the ST2 receptor, which subsequently leads to neutrophil recruitment or directly induces cellular damage through the release of intracellular Ca 2+ and the expression of FasL, thereby exacerbating renal injury ( 51 ). However, in a chronic, low-dose model of cisplatin-induced AKI in tumor-bearing mice, genetic deficiency of IL-33 did not provide functional or histological protection, suggesting that the IL-33/CD4 T-cell/CXCL1 axis may not be a major mediator in this more clinically relevant setting ( 52 ). In the folic acid (FA)-induced AKI model, IL-33 functions as a damage-associated molecular pattern (DAMP) and can be released extracellularly in a ferroptosis-dependent manner, thereby exerting a pro-inflammatory effect ( 53 ). However, the role of IL-33 in this model is not unidirectional. While its upregulation is associated with injury, studies have shown that genetic deletion of the necroptosis regulator receptor-interacting protein kinase 3 (RIPK3) did not attenuate IL-33 expression but did reduce other proinflammatory cytokines. This has led to the hypothesis that IL-33, in addition to being an early immune activator, may also play a role in immune regulation, potentially via Treg cells, to limit excessive inflammation and facilitate tissue repair ( 53 ). 3 The role of IL-33 in chronic kidney disease Research indicates that AKI significantly elevates the risk of developing CKD, which is characterized by organ fibrosis ( 54 ). In cases of CKD patients, there is a marked increase in the levels of IL-33 and its soluble decoy receptor sST2 ( 55 ). Notably, sST2 competes with the membrane-bound receptor ST2L for IL-33 binding, thereby functioning as a negative regulator of IL-33/ST2 signaling, which may modulate the net biological activity of IL-33 in the CKD setting. In the context of CKD, IL-33 interacts with the ST2L receptor, subsequently activating the NF-κB and MAPK signaling pathways via the classical MyD88-IRAK-TRAF cascade. This process aids in activating ILC2s, enhances the secretion of IL-5 and IL-13, and sustains the polarized state of M2 macrophages ( 56 ). M2 macrophages are capable of releasing mediators such as IL-10, arginase-1, and Areg, which contribute to anti-inflammatory effects and tissue repair ( 57 , 58 ). The IL-33/ST2 signaling axis has been linked to regulation of the transforming growth factor-beta (TGF-β) pathway, thereby driving renal epithelial-mesenchymal transition (EMT) and ultimately contributing to the progression of renal fibrosis ( 59 ). Research indicates that M2 macrophages may not only mitigate renal inflammation but also facilitate renal fibrosis through the secretion of TGF-β ( 58 , 60 , 61 ). This underscores the heterogeneous role of IL-33 in the pathophysiology of CKD. 3.1 The role of IL-33 in lupus nephritis Research indicates that sST2 and ST2L levels are markedly elevated in individuals with lupus nephritis (LN) ( 62 ). IL-33 interacts with ST2, facilitating both the clinical and pathological progression of LN ( 21 ). Systemic lupus erythematosus (SLE), an autoimmune disorder, frequently impacts the kidneys, leading to LN ( 63 ). The IL-33/ST2 signaling pathway has been demonstrated to stimulate plasmacytoid dendritic cells (pDCs) to produce substantial quantities of interferon-alpha (IFN-α) by altering neutrophil extracellular traps (NETs). This process exacerbates autoimmune inflammation and contributes to end-organ damage in SLE. Consequently, IL-33 potentially contributes to the neutrophil/NETs-IL-33/IFN-α pathway, further advancing renal inflammation ( 64 , 65 ). By contrast, serum sST2 levels were found to be significantly elevated in patients with active SLE compared with those with inactive disease and correlated with SLEDAI, anti-dsDNA antibody levels, and complement consumption, whereas circulating IL-33 levels showed no consistent association with disease activity ( 66 ). Clinical data show a positive correlation between IL-33/ST2 axis activation and LN severity, but mechanistic experiments establish a unidirectional cascade: nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) drives IL-33, while IL-33 knockdown does not affect NLRP3, excluding reciprocal feedback. Thus, the NLRP3/IL-33/ST2 axis represents linear forward signaling from NLRP3 to IL-33, not bidirectional crosstalk ( 62 ). Nevertheless, a growing body of evidence points to a protective function for IL-33 in certain pathological settings. For instance, in the NZB/W F1 murine model – a first-generation cross between New Zealand Black and New Zealand White strains that exhibits a pronounced susceptibility to lupus-like autoimmunity – early administration of recombinant IL-33 has been shown to markedly ameliorate proteinuria, prolong overall survival, and attenuate renal injury. This is achieved by enhancing the production of anti-dsDNA IgM antibodies, increasing the population of IL-10+ regulatory B cells, and inducing the expression of genes associated with M2 macrophages ( 67 ). Conversely, in the MRL-lpr model and the imiquimod (IMQ)-induced model, research indicates that ILC2s during autoimmune kidney disease diminish the increased expression of integrin α4β7 in healthy kidneys via Toll-like receptor 7/9 (TLR7/9) signaling. This process leads to the downregulation of cytokines, such as the regulatory protein Areg, thereby promoting renal inflammation. However, treatment with IL-33 has been shown to elevate the levels of α4β7 and Areg, thereby alleviating renal inflammation ( 68 ). 3.2 The role of IL-33 in IgA nephropathy B cell activating factor (BAFF), which is part of the tumor necrosis factor (TNF) superfamily, is key to controlling the maturation and differentiation of B lymphocytes. This cytokine exerts a profound influence on both the proliferative expansion and developmental progression of the B cell compartment ( 69 , 70 ). In BAFF-transgenic (BAFF-Tg) mice, excessive expression of IL-33 can elevate BAFF levels, leading to IgA nephropathy (IgAN) which involves circulating immune complexes and the deposition of immunoglobulins ( 71 , 72 ). Furthermore, administration of IL-33 may enhance IgA production by expanding ILC2s, thereby inducing immune complex deposition and exacerbating renal lesions ( 71 – 73 ). Additionally, elevated concentrations of BAFF can stimulate B cells to produce IgA immune complexes, which deposit in the glomeruli and interact with mesangial cells. Activated mesangial cells can recruit inflammatory cells, such as macrophages, to further promote glomerular damage and also cause injury to podocytes ( 73 , 74 ). It is important to note that while BAFF-Tg mice develop a form of IgAN involving circulating immune complexes and immunoglobulin deposition, this model primarily reflects pathology driven by BAFF overexpression and subsequent polyclonal B-cell hyperplasia ( 71 ). This differs from the current understanding of human IgAN pathogen
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