key: cord-0986741-w5xaom8w authors: Liang, Yuejin; Ge, Yiyue; Sun, Jiaren title: IL-33 in COVID-19: friend or foe? date: 2021-05-10 journal: Cell Mol Immunol DOI: 10.1038/s41423-021-00685-w sha: 5fcdb1cf915dc87fa86e72c120b8f7e5014a17af doc_id: 986741 cord_uid: w5xaom8w nan cytokines (IL-4, IL-9, IL-10, IL-13 and TGF-β). 7 Elevated type 2 cytokine levels correlated with an increased number of ILC2s in COVID-19 patients 3 and may contribute to the differentiation of pathogenic γδ T cells (IFN-γ low GM-CSF high ). Therefore, an elevation in IL-33 in the lungs following SAR-CoV-2 infection might be the driving force of type 2 immune cytokines and account for respiratory immune dysregulation. Moreover, IL-33dependent lung-resident ILC2s can modulate NK cell innate immunity by suppressing IFN-γ production and cytotoxic functions, 8 leading to an impaired NK cell responses against SARS-CoV-2 infection. In addition to NK cells, IL-33 inhibits innate immunity in respiratory viral infection by degrading IL-1 receptor-associated kinase (IRAK1) and viperin in plasmacytoid dendritic cells, leading to TLR7 hyporesponsiveness. 9 As TLR7 may be necessary for recognition of the SARS-CoV-2 genome and production of antiviral type I interferon, 10 IL-33 may dampen innate antiviral immunity and delay viral clearance in COVID-19 patients. Prominent neutrophil infiltration has been reported in severe COVID-19 patients, and a high neutrophil-to-lymphocyte ratio (NLR) is a predictor of in-hospital death. 11 Notably, IL-33 promotes rapid neutrophil migration via macrophage-derived CXCL1 and CXCL2, whereas neutrophil elastase and cathepsin G further contribute to IL-33 processing and maturation to exacerbate inflammatory responses. It is plausible that pathogenic γδ17 T cells may also accelerate neutrophil recruitment to the lungs via IL-17 production. Furthermore, immature neutrophils have been reported in severe COVID-19 cases. 12 Neutrophil dysregulation may be attributed to increased IL-33/ILC2 responses, since IL-33 can educate neutrophils towards a unique immunosuppressive phenotype via ILC2s and dampen the appropriate antiviral T cell immune response, 13 which is potentially involved in the control of SARS-CoV-2 infection. Importantly, elevated IL-33 levels and the associated type 2 immunity in chronic viral infection are considered potential inducers of pulmonary fibrosis, which is a recognized sequelae of acute respiratory distress syndrome (ARDS) observed in approximately 40% of COVID-19 patients. 14 Therefore, blockade of the IL-33/ neutrophil feedback loop using IL-33-or ST2-neutralizing antibodies might be a novel therapeutic strategy for severe COVID-19 patients. Encouragingly, a phase II clinical trial of Astegolimab (anti-ST2) treatment in patients with severe COVID-19 pneumonia is close to completion (ClinicalTrials.gov Identifier: NCT04386616). Although increased IL-33 levels are considered a predictor of severe COVID-19, their precise roles in different stages of disease are still unclear (Fig. 1B) . Individuals with relatively mild COVID-19 symptoms exhibit increased numbers of Treg cells, which are associated with the resolution of inflammation. In addition to proinflammatory activity, IL-33 may drive ST2 + regulatory T cell (Treg) expansion, inhibit innate γδ T cell responses, and restore respiratory tissue homoeostasis in patients who develop asymptomatic or mild disease. Notably, IL-33 is critical for antiviral CD8 T cell responses to persistent infection and may contribute to elimination of the virus. 15 Additional animal studies and clinical trials are essential for us to better understand the precise role of IL-33 and how manipulation of the IL-33/ST2 axis could be an effective therapeutic strategy for COVID-19 treatment. Interleukin-33 in health and disease Inflammatory phenotyping predicts clinical outcome in COVID-19 Severe COVID-19 patients exhibit an ILC2 NKG2D(+) population in their impaired ILC compartment Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity Transcriptomic characteristics of bronchoalveolar lavage fluid and peripheral blood mononuclear cells in COVID-19 patients IL-33 expression in response to SARS-CoV-2 correlates with seropositivity in COVID-19 convalescent individuals Imperfect storm: is interleukin-33 the Achilles heel of COVID-19? ILC2-driven innate immune checkpoint mechanism antagonizes NK cell antimetastatic function in the lung Aeroallergen-induced IL-33 predisposes to respiratory virusinduced asthma by dampening antiviral immunity Presence of genetic variants among young men with severe COVID-19 Neutrophil-to-lymphocyte ratio as an independent risk factor for mortality in hospitalized patients with COVID-19 Severe COVID-19 is marked by a dysregulated myeloid cell compartment IL-33 induces immunosuppressive neutrophils via a type 2 innate lymphoid cell/IL-13/STAT6 axis and protects the liver against injury in LCMV infection-induced viral hepatitis Pulmonary fibrosis secondary to COVID-19: a call to arms? The alarmin interleukin-33 drives protective antiviral CD8(+) T cell responses IL-33 in COVID-19: friend or foe? The authors of this work were supported by NIH grants, including EY028773 to J.S. and AI153586 to Y.L., and the UTMB Institute of Human Infections & Immunity Pilot grant to Y.L. We thank Dr. Sherry Haller and Dr. Hui Wang for their assistance with manuscript preparation. The image of Fig. 1B is created with BioRender.com. Y.G. designed and completed the in vitro experimental work. Y.L. and J.S. wrote this manuscript. All authors approved the manuscript. Competing interests: The authors declare no competing interests.