Journal Article

Nrf2 downregulates zymosan-induced neutrophil activation and modulates migration

Granger, Vanessa, Pallardy, Marc, Damien, Marie-Hélène, Kerdine-Römer, Saadia, De Chaisemartin, Luc, Helou, Doumet Georges, Chollet-Martin, Sylvie, Braham, Sarah

2019

Overview

Polymorphonuclear neutrophils (PMNs) are the first line of defense against pathogens and their activation needs to be tightly regulated in order to limit deleterious effects. Nrf2 (Nuclear factor (erythroïd-derived 2)-like 2) transcription factor regulates oxidative stress and/or represses inflammation in various cells such as dendritic cells or macrophages. However, its involvement in PMN biology is still unclear. Using Nrf2 KO mice, we thus aimed to investigate the protective role of Nrf2 in various PMN functions such as oxidative burst, netosis, migration, cytokine production and phagocytosis, mainly in response to zymosan. We found that zymosan induced Nrf2 accumulation in PMNs leading to the upregulation of some target genes including Hmox-1, Nqo1 and Cat. Nrf2 was able to decrease zymosan-induced PMN oxidative burst; sulforaphane-induced Nrf2 hyperexpression confirmed its implication. Tnfα, Ccl3 and Cxcl2 gene transcription was decreased in zymosan-stimulated Nrf2 KO PMNs, suggesting a role for Nrf2 in the regulation of proinflammatory cytokine production. However, Nrf2 was not involved in phagocytosis. Finally, spontaneous migration of Nrf2 KO PMNs was lower than that of WT PMNs. Moreover, in response to low concentrations of CXCL2 or CXCL12, Nrf2 KO PMN migration was decreased despite similar CXCR2 and CXCR4 expression and ATP levels in PMNs from both genotypes. Nrf2 thus seems to be required for an optimal migration. Altogether these results suggest that Nrf2 has a protective role in several PMN functions. In particular, it downregulates their activation in response to zymosan and is required for an adequate migration.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Antioxidants / Bernard, Claude (1813-1878) / Biochemistry, Molecular Biology / Biology and Life Sciences / Bone marrow / CCL3 protein / Cell activation / Cell Movement - immunology / Chemokines / CXCL12 protein / CXCR2 protein / CXCR4 protein / Cytokines / Dendritic cells / Diastereomers / Down-Regulation / EDTA / Female / Gene expression / Genes / Genotypes / Immunology / Inflammation / Leukocyte migration / Leukocytes (neutrophilic) / Leukocytes (polymorphonuclear) / Life Sciences / Low concentrations / Macrophages / Male / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Mice, Knockout / Neutrophil Activation - immunology / Neutrophils / Neutrophils - immunology / Neutrophils - physiology / NF-E2-Related Factor 2 - deficiency / NF-E2-Related Factor 2 - genetics / NF-E2-Related Factor 2 - immunology / Oxidative stress / Pathogenic microorganisms / Phagocytosis / Pneumonia / Production capacity / Research and Analysis Methods / Respiratory Burst / Sepsis / Streptococcus infections / Sulforafan / Sulforaphane / Transcription (Genetics) / Transcriptional Activation / Zymosan - immunology