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

Silvia Cellone Trevelin, Can Martin Sag, Min Zhang, José Carlos Alves-Filho, Thiago Mattar Cunha, Célio Xavier Dos Santos, Greta Sawyer, Thomas Murray, Alison Brewer, Francisco Rafael Martins Laurindo, Andrea Protti, Lucia Rossetti Lopes, Aleksandar Ivetic, Fernando Queiroz Cunha, Ajay M. Shah

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


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-α, 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-α 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-κB 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-κB activation and TLR4 expression, which in turn attenuates the severity of hypotension and systemic inflammation induced by LPS.

Original languageEnglish
Pages (from-to)268-277
Number of pages10
JournalShock (Augusta, Ga.)
Issue number2
Publication statusPublished - 1 Aug 2021


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