Endothelial Nox2 Limits Systemic Inflammation and Hypotension in Endotoxemia by Controlling Expression of Toll-Like Receptor 4

Author(s):Show less -

Trevelin, Silvia Cellone ^[1] ; Sag, Can Martin ^[2] ; Zhang, Min ^[1] ; Alves-Filho, Jose Carlos ^[3] ; Cunha, Thiago Mattar ^[3] ; Dos Santos, Celio Xavier ^[1] ; Sawyer, Greta ^[1] ; Murray, Thomas ^[1] ; Brewer, Alison ^[1] ; Martins Laurindo, Francisco Rafael ^[4] ; Protti, Andrea ^[1] ; Lopes, Lucia Rossetti ^[5] ; Ivetic, Aleksandar ^[1] ; Cunha, Fernando Queiroz ^[3] ; Shah, Ajay M. ^[1]

Affiliation

^[1] Kings Coll London, British Heart Fdn Ctr Res Excellence, Sch Cardiovasc Med & Sci, London - England

^[2] Univ Hosp Regensburg, Dept Internal Med 2, Regensburg - Germany

^[3] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ribeirao Preto - Brazil

^[4] Sch Med, Heart Inst, Sao Paulo - Brazil

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

• Document type: Journal article
• Source: Shock; v. 56, n. 2, p. 268-277, AUG 2021.
• Web of Science Citations: 1

Abstract

Leukocyte Nox2 is recognized to have a fundamental microbicidal function in sepsis but the specific role of Nox2 in endothelial cells (EC) remains poorly elucidated. Here, we tested the hypothesis that endothelial Nox2 participates in the pathogenesis of systemic inflammation and hypotension induced by LPS. LPS was injected intravenously in mice with Tie2-targeted deficiency or transgenic overexpression of Nox2. Mice with Tie2-targeted Nox2 deficiency had increased circulating levels of TNF-alpha, enhanced numbers of neutrophils trapped in lungs, and aggravated hypotension after LPS injection, as compared to control LPS-injected animals. In contrast, Tie2-driven Nox2 overexpression attenuated inflammation and prevented the hypotension induced by LPS. Because Tie2-Cre targets both EC and myeloid cells we generated bone marrow chimeric mice with Nox2 deletion restricted to leukocytes or ECs. Mice deficient in Nox2 either in leukocytes or ECs had reduced LPS-induced neutrophil trapping in the lungs and lower plasma TNF-alpha levels as compared to control LPS-injected mice. However, the pronounced hypotensive response to LPS was present only in mice with EC-specific Nox2 deletion. Experiments in vitro with human vein or aortic endothelial cells (HUVEC and HAEC, respectively) treated with LPS revealed that EC Nox2 controls NF-kappa B activation and the transcription of toll-like receptor 4 (TLR4), which is the recognition receptor for LPS. In conclusion, these results suggest that endothelial Nox2 limits NF-kappa B activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by LPS. (AU)

• FAPESP's process: 12/24677-7 - The role of Nox2 in endothelial dysfunction and failure of neutrophil migaration to focus of infection in sepsis
• Grantee: Silvia Cellone Trevelin
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate
• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC