2. Academic Validation
  3. PGE2/EP3/CXCR2 axis dictates amplified inflammatory response during skin infection in obese mice

PGE2/EP3/CXCR2 axis dictates amplified inflammatory response during skin infection in obese mice

  • J Invest Dermatol. 2025 Sep 30:S0022-202X(25)02476-5. doi: 10.1016/j.jid.2025.05.042.
Nathan Klopfenstein 1,  Ana Salina 2,  Amondrea Blackman 2,  David Aronoff 3,  Richard M Breyer 4,  C Henrique Serezani 5
Affiliations

Affiliations

  • 1 Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.
  • 2 Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.
  • 3 Department of Medicine, Indiana University School of Medicine and IU Health, Indianapolis, Indiana, United States of America.
  • 4 Department of Medicine, Nashville, Tennessee, United States of America.
  • 5 Department of Medicine, Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America; Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America; Vanderbilt Institute of Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America. Electronic address: h.serezan@vumc.org.
PMID: 41038339 DOI: 10.1016/j.jid.2025.05.042
Abstract

Skin infections caused by methicillin-resistant Staphylococcus aureus present significant complications for obese individuals. 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 (PGE2), 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 obese mice cannot control S. aureus skin infections, as evidenced by larger lesions, abscesses, and increased Bacterial load. The heightened susceptibility to Infection in obese mice is linked to decreased production of PGE2, 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 PGE2 levels with the FDA-approved PGE 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 obese mice. By uncovering both the therapeutic effects and the cellular mechanisms by which the PGE2/EP3 axis regulates the harmful inflammatory response, we advance the field, emphasizing its role in decreasing lesion size and improving host defense in preexisting conditions.

Keywords

Obesity; chemokine; macrophages; prostaglandin; skin infection.

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