However, to our knowledge, there is no data that explicitly study the immune-pathogenesis of IL-18, 1L-33, IL-36, IL-37, and IL-38 in the COVID-19. To date, several studies have been published about the pivotal role of IL-1 family cytokines in the cytokine storm. Mounting evidence accumulates that IL-1 family cytokines have a distinct role in disease pathogenesis. IL-1 family cytokines activate signal transduction by the IL-1 receptor (IL-1R) family, which consists of 10 members: IL-1R1, IL-1R2, IL-1R accessory protein (IL-1RAcP), IL-18Rα, IL-18Rβ, ST2 (or IL-33R), and IL-36R. The IL-1 family consists of 11 cytokines, seven with agonistic features (IL-1α, IL-1β, IL-18, IL-33, IL-36α, IL-36β, IL-36γ) and four with antagonistic features (IL-1 receptor antagonist (IL-1Ra), IL-36Ra, IL-37, IL-38). However, anti-inflammatory cytokines fail to preserve the pro‐/anti‐inflammatory proportion in the COVID-19 patients because of the overwhelming concentrations of pro-inflammatory cytokines, which are likely to trigger immune invasions, causing injuries to the healthy tissues. These altered cytokines include increased levels of both pro-and anti-inflammatory cytokines like interleukin (IL)-1 family, IL-6, interferons (IFNs), tumor necrosis factor (TNF), and C-reactive protein (CRP). Viral invasion by activating numerous immune mechanisms and immune cells such as monocytes (MOs), macrophages (MQs), dendritic cells (DCs), natural killer (NK) cells, B and T cells generates a disproportionate release of cytokines, known as cytokine storm. SARS-CoV-2 utilizes angiotensin-converting enzyme 2 (ACE2) to enter the cells and induce cellular injury, predominantly in the respiratory system. Hence, better perception of SARS-CoV-2 pathogenesis is contributed to the delineate proper therapeutic approaches. Nevertheless, some antiviral drugs associated with adverse side effects, therefore, numerous researches to find appropriate therapeutic strategies for this diseases alongside comprehensive vaccination are ongoing. For now, various therapeutic approaches, including antiviral therapeutics (Remdesivir, Opinavir/ritonavir, Tenofovir disoproxil fumarate, Chloroquine, etc.), and plasma therapies are consider as possible therapeutic options for COVID-19 treatment. Similar to their clinical presentations, SARS-CoV-2 infection accompanies by plethoric manifestations such as fatigue, fever, dyspnea, cough, diarrhea, and in severe cases with ARDS and multi-systemic dysfunctions. SARS-CoV-2 belongs to the beta-Coronaviruses and shares a similar genome with other members of this family, particularly Middle East respiratory syndrome coronavirus (MERS-CoV) and SARS-CoV, which were responsible for the outbreaks of CoVs in the past. This pandemic has posed catastrophic impacts on nations' healthcare resources, especially in regions with fragile healthcare infrastructures, such as Africa, Afghanistan, and Bangladesh, and overloaded healthcare systems due to the coexisting contagious disease, like Zika and Tuberculosis. SARS-CoV-2, the causative agent of the ongoing pandemic of COVID-19, has become a health threat since December 2019 and is responsible for over 500 million infected cases and 6 million deaths as of 6th May 2022. Here, the possible mechanisms and pathways involved in inflammatory immune responses are discussed. Hence, understanding the underlying inflammatory mechanism of these cytokines during infection is critical for reducing the symptoms and severity of the disease. Among these cytokines, interleukin (IL-) 1 family cytokines (IL-1, IL-18, IL-33, IL-36, IL-37, and IL-38) appear to have a strong inflammatory role in severe COVID-19. As excessive inflammatory responses are contributed to the severe stage of the COVID-19 disease, therefore, the pro-inflammatory cytokines are regarded as the Achilles heel during COVID-19 infection. Moreover, SARS-CoV-2 can induce uncontrolled inflammatory responses characterized by hyper-inflammatory cytokine production, which causes cytokine storm and acute respiratory distress syndrome (ARDS). Meantime, cytokines recognize as crucial components in guiding the appropriate immune pathways in the restraining and eradication of the virus. The antiviral immune response is an imperative factor in confronting the recent coronavirus disease 2019 (COVID-19) infections.

This pandemic has been consociated with widespread mortality worldwide. A global pandemic has erupted as a result of the new brand coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

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