Inflammation resolution: a dual-pronged approach to averting cytokine storms in COVID-19?

Abstract

Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation and potentially life-threatening "cytokine storms". Controlling the local and systemic inflammatory response in COVID-19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death ("debris")-induced "eicosanoid storm", including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID-19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on "anti-viral" and "anti-inflammatory" strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.

Keywords: COVID-19; Cytokine storms; Eicosanoid storm; Inflammation resolution; SARS-CoV-2.

Figures

Fig. 1

Inflammation resolution in severe COVID-19 infection. The left alveolus demonstrates (1) viral-induced alveolar cell death and the accumulation of apoptotic and necrotic cellular debris. This debris elicits a pro-inflammatory response from macrophages (2), which in turn produce high quantities of eicosanoids generating an “eicosanoid storm”. These eicosanoids subsequently stimulate the production of pro-inflammatory cytokines (3) by immune cells such as macrophages, generating a robust “cytokine storm” that in turn promotes further leukocytosis and immune cell infiltrates (4). This robust inflammatory response to viral infection promotes hyaline membrane formation (5) and subsequent acute respiratory distress syndrome. Tissue levels of SPMs and EETs are decreased in this robust inflammatory setting. The right alveolus demonstrates COVID-19 infection in the setting of active inflammation resolution mechanisms, as is the case in mild infection or potentially following treatment with SPMs or sEH inhibition to increase EETs. EETs promote the generation of SPMs from arachidonic acid and omega-3 fatty acids. SPMs (1) stimulate macrophage phagocytosis and efferocytosis, (2) decrease pro-inflammatory cytokine production, (3) inhibit leukocytosis and thereby decrease the inflammatory infiltrate, and (4) may stimulate the adaptive immune response and the production of anti-SARS-CoV-2 antibodies