The Reparative Roles of IL-33

Abstract

When discovered in the early 2000s, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. Yet research in other models has since revealed that IL-33 is a highly pleiotropic molecule with diverse functions. These activities are supported by elusive release mechanisms and diverse expression of the IL-33 receptor, STimulation 2 (ST2), on both immune and stromal cells. Interestingly, IL-33 also supports type 1 immune responses during viral and tumor immunity and after allogeneic hematopoietic stem cell transplantation. Yet the IL-33–ST2 axis is also critical to the establishment of systemic homeostasis and tissue repair and regeneration. Despite these recent findings, the mechanisms by which IL-33 governs the balance between immunity and homeostasis or can support both effective repair and pathogenic fibrosis are poorly understood. As such, ongoing research is trying to understand the potential reparative and regulatory versus pro-inflammatory and pro-fibrotic roles for IL-33 in transplantation. This review provides an overview of the emerging regenerative role of IL-33 in organ homeostasis and tissue repair as it relates to transplantation immunology. It also outlines the known impacts of IL-33 in commonly transplanted solid organs and covers the envisioned roles for IL-33 in ischemia-reperfusion injury, rejection, and tolerance. Finally, we give a comprehensive summary of its effects on different cell populations involved in these processes, including ST2+ regulatory T cells, innate lymphoid cell type 2, as well as significant myeloid cell populations.

Homeostasis and evolution in relation to regeneration and repair

“…DAMPS, damage-associated molecular patterns; EGF, epidermal growth factor; FGF, fibroblast growth factor; IL-33, interleukin-33; JAK/STAT, Janus kinase (JAK) signal transducer and activator of transcription (STAT) signalling pathway; GJp, gap junction proteins; pRb, retinoblastoma protein; TGF-β, transforming growth factor-β signalling; TLR, toll like receptor; VEGF, vascular endothelial growth factor; Wnt, Wnt signalling pathway; MAPK/ERK, mitogen-activated protein kinases (MAPK) signalling pathway shared by the extracellular signal-related kinase J Physiol 602.11 (ERK) cascade; MMPs, matrix metalloproteinases; Pten, phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase; c-myc, family of genes that make proteins that are involved in many cellular functions, such as cell multiplication, maturation and death; HIF, hypoxia-inducible factors; Hippo, hippo pathway and its downstream effectors, regulate organ growth and cell plasticity during animal development and regeneration; Nrf2, nuclear factor E (erythroid); p53, major tumour-suppressor gene; YAP, Hippo coactivators Yes-associated protein. Sequeira-Lopez, 2018;Huppert & Schwartz, 2023;Jacob et al, 2021;Jaźwińska & Sallin, 2016;Kostyuchenko& Kozin, 2021;Li 2023;Liang et al, 2021;Liu et al, 2022;Liu et al 2023;Molina & Cebrià, 2021;Ninov & Yun, 2015;Peiris & Oviedo, 2013;Popov & Petrov, 2014;Prudovsky, 2021;Slama et al, 2023;Saba & Turnquist, 2023;Wen et al, 2022;Wolff & Hinman, 2021;Zhang et al, 2022).…”

“…5) (Cadiz & Jonz, 2020; Calcinotto et al., 2019; Chen et al., 2019; D'Arpa & Leung, 2017; Gomes & Sequeira‐Lopez, 2018; Huppert & Schwartz, 2023; Jacob et al., 2021; Jaźwińska & Sallin, 2016; Kostyuchenko& Kozin, 2021; Li 2023; Liang et al., 2021; Liu et al., 2022; Liu et al. 2023; Molina & Cebrià, 2021; Ninov & Yun, 2015; Peiris & Oviedo, 2013; Popov & Petrov, 2014; Prudovsky, 2021; Slama et al., 2023; Saba & Turnquist, 2023; Wen et al., 2022; Wolff & Hinman, 2021; Zhang et al., 2022).…”

“…The mechanisms by which IL‐33 balances immunity and homeostasis or support effective repair or pathogenic fibrosis are poorly understood. IL‐33 has potent repair capabilities and is critical for homeostasis (Saba & Turnquist, 2023).…”

Tregs in transplantation tolerance: role and therapeutic potential

“…It has been shown in cancer, allergy, and lung injury that IL-33, an alarmin expressed at higher levels during inflammation (132,133), promotes tissue repair and a more suppressive phenotype in ST2 + Tregs (134)(135)(136)(137)(138). However, IL-33 in the contexts of transplantation and GVHD has pleiotropic effects; there is evidence of IL-33 promoting Treg expansion, but IL-33 also has been shown to act as a costimulatory molecule for alloreactive Tconvs (138)(139)(140)(141)(142). In a GVHD model, IL-33/ST2 signaling in CD4 + cells promoted expansion and led to upregulation of Tbet while inhibiting IL-10 and Foxp3 expression which led to an exacerbation of GVHD severity (142,143).…”

Roles of IL-33 in the Pathogenesis of Cardiac Disorders

“…When discovered, interleukin-33 (IL-33) was characterized as a potent driver of type 2 immunity and implicated in parasite clearance, as well as asthma, allergy, and lung fibrosis. 6 IL-33 plays a fundamental role in tissue repair, fibrosis, immune rejection, and homeostasis, as the importance of type 2 response has emerged. 4 In addition, IL-33 can be expressed in different parenchymal cells and play different roles in different tissues and organs.…”