Hypoxia enhances ILC3 responses through HIF-1 alpha-dependent mechanism

Author(s):Show less -

Fachi, J. L. ^{[1, 2]} ; Pral, L. P. ^[2] ; dos Santos, J. A. C. ^[2] ; Codo, A. C. ^[3] ; de Oliveira, S. ^[2] ; Felipe, J. S. ^[2] ; Zambom, F. F. F. ^[4] ; Camara, N. O. S. ^{[5, 4]} ; Vieira, P. M. M. M. ^{[6, 7, 3]} ; Colonna, M. ^[1] ; Vinolo, M. A. R. ^{[6, 2, 7]}

Affiliation

^[1] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO 63130 - USA

^[2] Univ Estadual Campinas, Inst Biol, Dept Genet Evolut Microbiol & Immunol, Lab Immunoinflammat, Campinas - Brazil

^[3] Univ Estadual Campinas, Inst Biol, Dept Genet & Evolut Microbiol & Immunol, Lab Immunometabolism, Campinas - Brazil

^[4] Univ Sao Paulo, Fac Med, Dept Clin Med, Renal Div, Sao Paulo - Brazil

^[5] Univ Sao Paulo, Inst Biomed Sci, Dept Immunol, Sao Paulo - Brazil

^[6] Expt Med Res Cluster, Campinas - Brazil

^[7] Univ Estadual Campinas, Obes & Comorbol Res Ctr OCRC, Campinas - Brazil

• Document type: Journal article
• Source: MUCOSAL IMMUNOLOGY; v. 14, n. 4 JAN 2021.
• Web of Science Citations: 1

Abstract

Group 3 innate lymphoid cells (ILC3) have a prominent role in the maintenance of intestine mucosa homeostasis. The hypoxia-inducible factor (HIF) is an important modulator of immune cell activation and a key mechanism for cellular adaptation to oxygen deprivation. However, its role on ILC3 is not well known. In this study, we investigated how a hypoxic environment modulates ILC3 response and the subsequent participation of HIF-1 signaling in this process. We found increased proliferation and activation of intestinal ILC3 at low oxygen levels, a response that was phenocopied when HIF-1 alpha was chemically stabilized and was reversed when HIF-1 was blocked. The increased activation of ILC3 relied on a HIF-1 alpha-dependent transcriptional program, but not on mTOR-signaling or a switch to glycolysis. HIF-1 alpha deficiency in RORyt compartment resulted in impaired IL-17 and IL-22 production by ILC3 in vivo, which reflected in a lower expression of their target genes in the intestinal epithelium and an increased susceptibility to Clostridiodes difficile infection. Taken together, our results show that HIF-1 alpha activation in intestinal ILC3 is relevant for their functions in steady state and infectious conditions. (AU)

• FAPESP's process: 15/15626-8 - Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases
• Grantee: Pedro Manoel Mendes de Moraes Vieira
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 19/11662-0 - Participation of the FFAR2 receptor in the inflammation in a DSS-induced colitis model
• Grantee: Sarah de Oliveira
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/22505-0 - Effect of 12-oleic acid ester of hydroxy fatty acid (12-OAHSA) on inflammatory and metabolic pathways of macrophage activation
• Grantee: Ana Campos Codo
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• FAPESP's process: 18/02208-1 - Effect of short chain fatty acids on the function of type 3 innate lymphoid cells: involvement of the FFAR2 receptor in this process
• Grantee: Laís Passariello Pral
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 17/06577-9 - Mechanisms involved in the protective effect of short-chain fatty acids against Clostridium difficile-associated colitis
• Grantee: José Luís Fachi
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 19/06372-3 - Multiparametric flow cytometry
• Grantee: Alessandro dos Santos Farias
• Support Opportunities: Multi-user Equipment Program
• FAPESP's process: 17/16280-3 - Role of the interaction between HIF-1 and the short chain fatty acids in the colon in physiological and pathologycal conditions (intestinal inflammation)
• Grantee: Marco Aurélio Ramirez Vinolo
• Support Opportunities: Regular Research Grants