PGE₂/EP3/CXCR2 Axis Dictates Amplified Inflammatory Response during Skin Infection in Mice with Obesity

Skin infections caused by methicillin-resistant Staphylococcus aureus present significant complications for individuals with obesity. However, the factors driving the dysregulated skin host defense and injury in these individuals remain unclear. In this study, we investigated a dysregulated molecular checkpoint, prostaglandin E₂, which fails to prevent the inflammatory response from damaging infected skin during obesity, resulting in poor bacterial clearance and larger lesions. Our data show that mice with obesity cannot control S aureus skin infections, as evidenced by larger lesions, abscesses, and increased bacterial load. The heightened susceptibility to infection in mice with obesity is linked to decreased production of prostaglandin E₂, lower levels of CXC chemokines, and reduced recruitment of CXCR2+ phagocytes to the infected skin. Through epistatic and gain-of-function approaches, our data demonstrate that restoring prostaglandin E₂ levels with the Food and Drug Administration-approved prostaglandin E analog misoprostol reduces tissue injury and enhances bacterial clearance, acting through E-prostanoid 3-mediated cAMP inhibition that reinstates the CXC-family/CXCR2 axis in infected mice with obesity. By uncovering both the therapeutic effects and the cellular mechanisms through which the prostaglandin E₂/EP3 axis regulates the harmful inflammatory response, we advance the field, emphasizing its role in decreasing lesion size and improving host defense in pre-existing conditions.