The authors discovered the important role that lipid mediators (resolvin D4 in this study) play in both formation and resolution of clots in deep vein thrombosis.

Rationale: Resolution mechanisms are central in both the maintenance of homeostasis and the return to catabasis following tissue injury and/or infections. Amongst the pro-resolving mediators, the essential fatty acid-derived specialized pro-resolving lipid mediators (SPM) govern immune responses to limit disease severity. Notably, little is known about the relationship between the expression and activity of SPM pathways, circulating phagocyte function and disease severity in patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leading to coronavirus disease 2019 (COVID-19). Objective: Herein, we investigated the link between circulating SPM concentrations and phagocyte activation status and function in COVID-19 patients (n=39) compared to healthy (n=12) and post-COVID-19 (n=8) volunteers. Methods and Results: Lipid mediator profiling demonstrated that plasma SPM concentrations were upregulated in patients with mild COVID-19 and are downregulated in those with severe disease. SPM concentrations were correlated with both circulating phagocyte activation status and function. Perturbations in plasma SPM concentrations and phagocyte activation were retained after the resolution of COVID-19 clinical symptoms. Treatment of patients with dexamethasone upregulated both the expression of SPM biosynthetic enzymes in circulating phagocytes and plasma concentration of these mediators. Furthermore, incubation of phagocytes from COVID-19 patients with SPM rectified their phenotype and function. This included a downregulation in the expression of activation markers, a decrease in the Tissue Factor and inflammatory cytokine expression, and an upregulation of bacterial phagocytosis. Conclusions: The present findings suggest that downregulation of systemic SPM concentrations is linked with both increased disease severity and dysregulated phagocyte function. They also identify the upregulation of these mediators by dexamethasone as a potential mechanism in host protective activities elicited by this drug in COVID-19 patients. Taken together, our findings elucidate a role for altered resolution mechanisms in the disruption of phagocyte responses and the propagation of systemic inflammation in COVID-19.

Excessive chronic inflammation is linked to many diseases and considered a stress factor in humans (Robbins Pathologic Basis of Disease. Philadelphia: W.B. Saunders Co., 1999, Proc Natl Acad Sci USA, 2008, 105: 17949, Immunity, 44, 2016, 44: 463, N Engl J Med, 2011, 364: 656). Today, the resolution of inflammation is widely recognized as a cellular biochemically active process involving biosynthesis of a novel superfamily of endogenous chemical signals coined specialized pro‐resolving mediators (SPMs; Nature, 2014, 510:92). Herein, we review recent evidence, indicating a role for the vagus nerve and vagotomy in the regulation of lipid mediators. Vagotomy reduces pro‐resolving mediators, including the lipoxins, resolvins, protectins and maresins, delaying resolution in mouse peritonitis. Vagotomy also delays resolution of Escherichia coli infection in mice. Specifically, right vagus regulates peritoneal Group 3 innate lymphoid cell (ILC‐3) number and peritoneal macrophage responses with lipid mediator profile signatures with elevated pro‐inflammatory eicosanoids and reduced resolvins, including the novel protective immunoresolvent agonist protectin conjugate in tissue regeneration1 (PCTR1). Acetylcholine upregulates PCTR biosynthesis, and administration of PCTR1 to vagotomized mice restores tissue resolution and host responses to E. coli infections. Results obtained with human vagus ex vivo indicate that vagus can produce both pro‐inflammatory eicosanoids, such as prostaglandins and leukotrienes, as well as the SPM. Electrical stimulation of human vagus in vitro reduces both prostaglandins and leukotrienes and enhances resolvins and the other SPM. These results elucidate a host protective mechanism mediated by vagus stimulation of SPM that includes resolvins and PCTR1 to regulate myeloid antimicrobial functions and resolution of infection. Moreover, they define a new pro‐resolution of inflammation reflex operative in mice and human tissue that involves a vagus SPM circuit.