Open camera or QR reader and scan code to access this article and other resources online. Interleukin-1 in COVID-19 Infection: Immunopathogenesis and Possible Therapeutic Perspective Amirhossein Mardi, 1 Sepideh Meidaninikjeh, 2 Sepideh Nikfarjam, 3 Naime Majidi Zolbanin, 4,5 and Reza Jafari 6,i Abstract The newfound coronavirus disease 2019 (COVID-19), initiated by severe acute respiratory syndrome corona- virus 2 (SARS-CoV-2), is an international public health concern, threatening the lives of millions of people world- wide. The virus seems to have a propensity to infect older males, especially those with underlying diseases. The cytokine storm following hyperactivated immune responses due to SARS-CoV-2 infection is probably the cru- cial source of severe pneumonia that leads to acute lung injury, systemic inflammatory response syndrome, or acute respiratory distress syndrome, and finally multiple organ dysfunction syndromes, as well as death in many cases. Several studies revealed that interleukin (IL)-1b levels were elevated during COVID-19 infection. In addition, the IL-1 cytokine family has a pivotal role in the induction of cytokine storm due to uncontrolled immune responses in COVID-19 infection. This article reviews the role of IL-1 in inflammation and utiliza- tion of IL-1 inhibitor agents in controlling the inflammatory outcomes initiated by SARS-CoV-2 infection. Keywords: COVID-19, SARS-CoV-2, IL-1, cytokine inhibitors Introduction C oronavirus disease 2019 (COVID-19) is currently a global pneumonia pandemic triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (60). The first cases of SARS-CoV-2 infection were reported in a shellfish market in December 2019 in south Wuhan, China (27). The World Health Organization declared the COVID-19 outbreak as a pandemic situation on the 11th of March 2020. Interleukin (IL)-1b is the most investigated member of the IL-1 family (IL-1F) because of its functions in regulating autoinflammatory diseases. IL-1b has an effective pyrogenic effect. It stimulates immune cells and increases the upregu- lation of adhesion molecules on endothelial cells, thus pro- moting activated immune cells such as neutrophils to migrate to the infection sites (29). IL-1b can be produced from sev- eral cell types. Blood monocytes, dendritic cells, and tis- sue macrophages are the main sources of IL-1b in the body. IL-1b is also produced by NK cells and B lymphocytes (15). IL-1b can induce the expression of multiple genes that reg- ulate fever, hypotension, pain threshold, and vasodilatation (64). Unlike other cytokines, IL-1F members act indirectly in the immune system. For example, IL-1b promotes the induction of type 2 phospholipase A, cyclooxygenase type 2, inducible nitric oxide (NO) synthase, which accounts for platelet-activating factor, prostaglandin E2, and NO synth- esis, respectively (15). During the activation of pattern recognition receptors (PRRs), which recognize pathogen- or damage-associated molecular patterns (PAMPs or DAMPs), IL-1b is produced by tissue-resident macrophages. The most important PRR in macrophages is the intracellular NLRP3 (NOD-like, leucine- rich repeat domains, and pyrin domain-containing protein 3). NLRP3 acts as a latent monomer in inactive cells. Several signals are necessary for the activation of the NLRP3 in- flammasome. Once stimulated, NLRP3 employs procaspase 1 Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 2 Department of Microbiology, Faculty of Biological Sciences, Alzahra University, Tehran, Iran. 3 Department of Anatomy and Cell Biology, Schulich School of Medicine and Dentistry,University of Western Ontario, London, ON, Canada. 4 Experimental and Applied Pharmaceutical Research Center, 5 Department of Pharmacology and Toxicology, Faculty of Pharmacy, and 6 Nephrology and Kidney Transplant Research Center, Clinical Research Institute, Urmia University of Medical Sciences, Urmia, Iran. i ORCID ID (https://orcid.org/0000-0003-2036-9043). VIRAL IMMUNOLOGY Volume 34, Number 10, 2021 ª Mary Ann Liebert, Inc. Pp. 1–10 DOI: 10.1089/vim.2021.0071 1 Downloaded by 3.239.7.17 from www.liebertpub.com at 12/18/21. For personal use only.