Nrf2 downregulates zymosan-induced neutrophil activation and modulates migration

Abstract

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.

Sulforaphane Elicits Protective Effects in Intestinal Ischemia Reperfusion Injury

“…For leukocytes, it has been shown that SFN is able to alter leukocyte adhesion. Moreover, it is suggested to play a role in the regulation of pro-inflammatory cytokines and, through the role as Nrf2-agonist, required for optimal migration of neutrophils [40]. In accordance with the here presented data, a study of LPS-induced inflammation in the brain could show a decrease in leukocyte adherence as well as reduced MPO levels after pre-treatment with SFN [41].…”

“…While leukocyte recruitment is an important aspect in inflammatory response, excessive accumulation during I/R contributes to pathological conditions [38,39]. Recent studies have shown the ability of SFN to affect cells of the innate immune system including neutrophils and platelets that are known as the first line defense following injury [20,40]. For leukocytes, it has been shown that SFN is able to alter leukocyte adhesion.…”

Intranasal vaccine from whole Leishmania donovani antigens provides protection and induces specific immune response against visceral leishmaniasis

“…Cells were collected from the femur and tibia and resuspended in PBS solution containing 0.5% bovine serum albumin (BSA) and 2 mM Ethylene diamine tetraacetic acid (EDTA) [ 28 , 29 ]. Collected cells were filtrated through 70 μM pre-separation filters to remove cell aggregates or large particles.…”

Electrophiles against (Skin) Diseases: More Than Nrf2

“…In addition, NRF2 activators inhibit also the transcriptional activity of NF-κB and the inflammasome pathway (see below) [19,22]. The expression and activity of NRF2 is very high in immune cells, which are frequently exposed to oxidative stress, particularly upon induction of the oxidative burst during phagocytosis of pathogens [47]. However, epithelial keratinocytes also express high levels of NRF2 and the transcription factor is critically involved in wound healing [4], UV protection [3,5], skin cancer development [48] and several severe autoimmune diseases with skin involvement, such as systemic lupus erythematosus, Sjogren's syndrome and vitiligo [19].…”