A novel murine model of pyoderma gangrenosum reveals that inflammatory skin-gut crosstalk is mediated by IL-1β-primed neutrophils

Frontiers in Immunology

Immunology

Edward V. Maytin¹  András K. Ponti²  Nancy A. Rebert²  Jordyn L. Smith²  Samreen Jatana²  Erin E. Johnson³  Jean-Paul Achkar⁴  Christine McDonald⁵  Clifton G. Fulmer⁶  Anthony P. Fernandez⁷ 

[1] Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Dermatology, Dermatology & Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Biology, John Carroll University, University Heights, OH, United States;Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Gastroenterology, Digestive Diseases and Surgery Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH, United States;Department of Pathology, Pathology & Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States;Department of Pathology, Pathology & Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States;Department of Dermatology, Dermatology & Plastic Surgery Institute, Cleveland Clinic, Cleveland, OH, United States;

关键词: pyoderma gangrenosum (PG);    inflammatory bowel disease (IBD);    neutrophil extracellular traps (NETs);    neutrophilic dermatosis;    skin-gut crosstalk;    pyrimidine synthesis;    skin ulcers;   

DOI  :  10.3389/fimmu.2023.1148893

 received in 2023-01-20, accepted in 2023-06-08,  发布年份 2023

来源: Frontiers

【 摘 要 】

Pyoderma gangrenosum (PG) is a debilitating skin condition often accompanied by inflammatory bowel disease (IBD). Strikingly, ~40% of patients that present with PG have underlying IBD, suggesting shared but unknown mechanisms of pathogenesis. Impeding the development of effective treatments for PG is the absence of an animal model that exhibits features of both skin and gut manifestations. This study describes the development of the first experimental drug-induced mouse model of PG with concomitant intestinal inflammation. Topical application of pyrimidine synthesis inhibitors on wounded mouse skin generates skin ulcers enriched in neutrophil extracellular traps (NETs) as well as pro-inflammatory cellular and soluble mediators mimicking human PG. The mice also develop spontaneous intestinal inflammation demonstrated by histologic damage. Further investigations revealed increased circulating low density IL-1β primed neutrophils that undergo enhanced NETosis at inflamed tissue sites supported by an increase in circulatory citrullinated histone 3, a marker of aberrant NET formation. Granulocyte depletion dampens the intestinal inflammation in this model, further supporting the notion that granulocytes contribute to the skin-gut crosstalk in PG mice. We anticipate that this novel murine PG model will enable researchers to probe common disease mechanisms and identify more effective targets for treatment for PG patients with IBD.

【 授权许可】

Unknown   
Copyright © 2023 Jatana, Ponti, Johnson, Rebert, Smith, Fulmer, Maytin, Achkar, Fernandez and McDonald