Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in severely ill patients and the pathophysiology of disease is thought to be immune-mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens, often promoting inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and non-human primates. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype. MC activation in humans was confirmed, through detection of the MC-specific protease, chymase, levels of which were significantly correlated with disease severity. These results support the association of MC activation with severe COVID-19, suggesting potential strategies for intervention.
Inflammatory diseases change tissue metabolism, resulting in alterations in extracellular adenine nucleotide regulation and a resultant protective influence of adenosine (Ado). We hypothesized that Ecto‐5′‐nucleotidase (CD73), a central surface enzyme in the generation of extracellular Ado, is protective in mucosal inflammation as modeled by TNBS colitis. Initial studies revealed a greater than 3‐fold increase in CD73 mRNA levels following induction of TNBS colitis. We further demonstrate more severe colitis, as determined by weight loss and colonic shortening, in cd73−/− mice relative to cd73+/+ controls. Likewise, systemic administration of the selective CD73 inhibitor APCP to cd73+/+ mice resulted in a similar increase in severity of TNBS colitis. Gene array profiling of cytokine‐associated mRNA expression revealed a greater than 90% down‐regulation of IFNαA in cd73−/− compared to cd73+/+ mice. Real‐time PCR verified this profound colonic IFNαA down‐regulation in both cd73−/− mice and APCP‐treated cd73+/+ mice. Finally, exogenous administration of recombinant IFNαA partially protected cd73−/− mice from disease severity in colitis. Together, these studies indicate a critical regulatory role for CD73‐modulated IFNαA in the acute inflammatory phase of TNBS colitis, and implicate IFNαA as a protective element of Ado signalling during mucosal inflammation.
Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
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