Prolonged exposure to lung-derived cytokines is associated with activation of microglia in patients with COVID-19
Neurological impairment is the most common finding in patients with post-acute sequelae of COVID-19. Furthermore, survivors of pneumonia from any cause have an elevated risk of dementia. In rodent models, cognitive dysfunction following pneumonia has been linked to the release of pro-inflammatory cytokines from the injured lung. As the primary immune cell in the brain, microglia are poised to respond to inflammatory signals from the circulation, and dysfunction in microglia has been linked to cognitive impairment in murine models of dementia and in humans. Here, we report a transcriptional response in human microglia collected from patients who died following COVID-19 suggestive of their activation by TNF-? and other circulating pro-inflammatory cytokines. Consistent with these findings, the levels of 55 alveolar and plasma cytokines were elevated in a cohort of 341 patients with respiratory failure, including 93 unvaccinated patients with COVID-19 and 203 patients with other causes of pneumonia. While peak levels of pro-inflammatory cytokines were similar in patients with pneumonia irrespective of etiology, cumulative cytokine exposure was higher in patients with COVID-19. Corticosteroid treatment, which has been shown to be beneficial in patients with COVID-19, was associated with lower levels of CXCL10, CCL8, and CCL2—molecules that sustain inflammatory circuits between alveolar macrophages harboring SARS-CoV-2 and activated T cells. These findings suggest that corticosteroids may break this cycle and decrease systemic exposure to lung-derived cytokines and inflammatory activation of microglia in patients with COVID-19. Overall design: We flow-cytometry sorted neuroimmune cells from brain samples obtained at autopsy from 5 patients who died from COVID-19 and 3 patients who died from other causes for single-cell RNA-sequencing.