Differential recognition of C. neoformans by male and female human macrophages elicits contrasting immune responses

In contrast, female macrophages secreted fewer proinflammatory cytokines at both 24 and 48 h but had increased secretion of CCL5 (24 and 48 h) and IL-18 (48 h). As male macrophages rapidly downregulated proinflammatory immune responses after 24 h; we investigated the macrophage activation state. Male macrophages were alternatively activated at 48 h, with increased secretion of arginase 1 whereas female macrophages were classically activated, with increased secretion of nitric oxide at 24 and 48 h.

Cn genes related to glucuronoxylomannan (GXM) biosynthesis were increased in Cn grown in male serum at 48 h. These data suggest that female macrophages better recognize Cn and become classically activated whereas male macrophages initiate an inflammatory response that is markedly reduced after 24 h, possibly due to testosterone-induced GXM secretion. Therefore, antifungal therapeutics targeting testosterone-induced GXM release may improve outcomes in male patients with cryptococcosis.