NKp46+ILC3s promote early neutrophil defense against Clostridioides difficile infection through GM-CSF secretion

Autor(es)

Fachi, Jose L. ; de Oliveira, Sarah ; Gilfillan, Susan ; Antonova, Alina Ulezko ; Hou, JinChao ; Vinolo, Marco A. R. ; Colonna, Marco

• Tipo de documento: Artigo Científico
• Fonte: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA; v. 121, n. 45, p. 10-pg., 2024-11-05.

Resumo

Clostridioides difficile infection (CDI) is a common cause of antibiotic- associated colitis. C. difficile proliferates and produces toxins that damage the colonic epithelium, leading to symptoms ranging from mild diarrhea to severe pseudomembranous colitis. The host's innate response to CDI occurs in two phases: an early phase in which neutrophils reduce the bacterial load and a late phase involving repair mechanisms to restore epithelial integrity. Group 3 innate lymphoid cells (ILC3s) are crucial in protecting the gut from CDI. Previous studies have shown that ILC3- derived IL- 22 is essential in the late phase of CDI for epithelial repair and maintaining an intestinal microbiota that competes with C. difficile, preventing its expansion. Our study finds that ILC3s also protect during the early stages of CDI by sustaining neutrophils through GM-CSF. Less neutrophil production, accumulation, and activation was evident in ILC3- deficient mice than in wild- type (WT) mice, which led to exacerbated symptoms, impaired pathogen clearance, a compromised epithelial barrier, and increased mortality. The adoptive transfer of ILC3s into ILC3- deficient mice restored neutrophil responses and improved disease outcomes. Both in vitro and in vivo experiments revealed that GM-CSF production by ILC3s is crucial for neutrophil production and effective resistance during CDI. Using mice lacking NKp46+ILC3s, we found that this subset significantly contributes to GM-CSF production in CDI. These findings highlight the critical role of the ILC3- neutrophil connection in early innate responses to CDI. Enhancing ILC3 production of GM-CSF could be a promising strategy for improving host defense against CDI and other enteric infections. (AU)

• Processo FAPESP: 21/09155-3 - Análise do papel do receptor FFAR2 na funcionalidade e mielopoiese de neutrófilos
• Beneficiário: Sarah de Oliveira
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 17/06577-9 - Mecanismos envolvidos no efeito protetor dos ácidos graxos de cadeia curta frente à colite associada ao Clostridium difficile
• Beneficiário: José Luís Fachi
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 18/15313-8 - Análise dos mecanismos moleculares envolvidos na interação de metabólitos da microbiota e células do hospedeiro durante a inflamação
• Beneficiário: Marco Aurélio Ramirez Vinolo
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores - Fase 2
• Processo FAPESP: 23/00393-4 - Papel do eixo acetato-FFAR2 na granulopoiese e na produção de IL-22 por neutrófilos intestinais
• Beneficiário: Sarah de Oliveira
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado