Testosterone and estradiol reduce inflammation of human macrophages induced by anti‐SARS‐CoV‐2 IgG

COVID‐19, the disease caused by SARS‐CoV‐2, particularly causes severe inflammatory disease in elderly, obese, and male patients. Since both aging and obesity are associated with decreased testosterone and estradiol expression, we hypothesized that decreased hormone levels contribute to excessive inflammation in the context of COVID‐19. Previously, we and others have shown that hyperinflammation in severe COVID‐19 patients is induced by the production of pathogenic anti‐spike IgG antibodies that activate alveolar macrophages. Therefore, we developed an in vitro assay in which we stimulated human macrophages with viral stimuli, anti‐spike IgG immune complexes, and different sex hormones. Treatment with levels of testosterone reflecting young adults led to a significant reduction in TNF and IFN‐γ production by human macrophages. In addition, estradiol significantly attenuated the production of a very broad panel of cytokines, including TNF, IL‐1β, IL‐6, IL‐10, and IFN‐γ. Both testosterone and estradiol reduced the expression of Fc gamma receptors IIa and III, the two main receptors responsible for anti‐spike IgG‐induced inflammation. Combined, these findings indicate that sex hormones reduce the inflammatory response of human alveolar macrophages to specific COVID‐19‐associated stimuli, thereby providing a potential immunological mechanism for the development of severe COVID‐19 in both older male and female patients. Older and obese individuals are at greater risk of developing severe COVID‐19. In this paper, we identified that this may be related to decreased levels of testosterone and estradiol, by showing that these sex hormones reduce the excessive production of proinflammatory cytokines induced by anti‐SARS‐CoV‐2 IgG antibodies.