1. PTPN2 regulates bacterial clearance in a mouse model of enteropathogenic and enterohemorrhagic E. coli infection
- Author
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Spalinger, Marianne R, Canale, Vinicius, Becerra, Anica, Shawki, Ali, Crawford, Meli’sa, Santos, Alina N, Chatterjee, Pritha, Li, Jiang, Nair, Meera G, and McCole, Declan F
- Subjects
Medical Microbiology ,Biomedical and Clinical Sciences ,Biodefense ,Emerging Infectious Diseases ,Foodborne Illness ,Infectious Diseases ,Digestive Diseases ,2.1 Biological and endogenous factors ,2.2 Factors relating to the physical environment ,Infection ,Inflammatory and immune system ,Animals ,Humans ,Mice ,Enterobacteriaceae Infections ,Enterohemorrhagic Escherichia coli ,Epithelial Cells ,Escherichia coli Infections ,Protein Tyrosine Phosphatase ,Non-Receptor Type 2 ,Bacterial infections ,Cellular immune response ,Gastroenterology ,Inflammation ,Macrophages ,Biomedical and clinical sciences ,Health sciences - Abstract
Macrophages intimately interact with intestinal epithelial cells, but the consequences of defective macrophage-epithelial cell interactions for protection against enteric pathogens are poorly understood. Here, we show that in mice with a deletion in protein tyrosine phosphatase nonreceptor type 2 (PTPN2) in macrophages, infection with Citrobacter rodentium, a model of enteropathogenic and enterohemorrhagic E. coli infection in humans, promoted a strong type 1/IL-22-driven immune response, culminating in accelerated disease but also faster clearance of the pathogen. In contrast, deletion of PTPN2 specifically in epithelial cells rendered the epithelium unable to upregulate antimicrobial peptides and consequently resulted in a failure to eliminate the infection. The ability of PTPN2-deficient macrophages to induce faster recovery from C. rodentium was dependent on macrophage-intrinsic IL-22 production, which was highly increased in macrophages deficient in PTPN2. Our findings demonstrate the importance of macrophage-mediated factors, and especially macrophage-derived IL-22, for the induction of protective immune responses in the intestinal epithelium, and show that normal PTPN2 expression in the epithelium is crucial to allow for protection against enterohemorrhagic E. coli and other intestinal pathogens.
- Published
- 2023