Circ Res . Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in Covid-19

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Circ Res


. 2021 Jul 9.
doi: 10.1161/CIRCRESAHA.121.319142. Online ahead of print.
Disrupted Resolution Mechanisms Favor Altered Phagocyte Responses in Covid-19


Duco Koenis ¹ , Issa Beegun ² , Charlotte Jouvene ³ , Gabriel Amador Aguirre ⁴ , Patricia R Souza ⁵ , Maria Gonzalez-Nunez ⁵ , Lucy Ly ⁶ , Kimberly Pistorius ⁵ , Hemant M Kocher ⁷ , William Ricketts ⁸ , Gavin Thomas ⁹ , Mauro Perretti ⁵ , Ghassan Alusi ⁵ , Paul Pfeffer ¹⁰ , Jesmond Dalli ⁵



Affiliations

• PMID: 34238021
• DOI: 10.1161/CIRCRESAHA.121.319142

Abstract

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.

Keywords: GPCR; leukocytes; lipid mediators; omega-3 fatty acids; resolvin.