Journal
JOURNAL OF IMMUNOLOGY
Volume 185, Issue 1, Pages 569-577Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0902315
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Funding
- National Institutes of Health [GM079239, HL081205]
- National Heart, Lung, and Blood Institute [P50HL084945]
- Center for Childhood Asthma in the Urban Environment [P50ES015903]
- National Institute on Environmental Health Sciences Center [P30 ES003819]
- Flight Attendant Medical Research Institute
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Sepsis syndrome is characterized by a dysregulated inflammatory response to infection. NADPH oxidase-dependent reactive oxygen species (ROS) play significant roles in the pathophysiology of sepsis. We previously showed that disruption of Nrf2, a master regulator of antioxidant defenses, caused a dysregulation of innate immune response that resulted in greater mortality in a polymicrobial sepsis and LPS shock model; however, the underlying mechanisms are unclear. In the current study, compared with wild-type (Nrf2(+/+)) macrophages, we observed greater protein kinase C-induced NADPH oxidase-dependent ROS generation in Nrf2-disrupted (Nrf2(-/-)) macrophages that was modulated by glutathione levels. To address the NADPH oxidase-mediated hyperinflammatory response and sepsis-induced lung injury and mortality in Nrf2(-/-) mice, we used double knockout mice lacking Nrf2 and NADPH oxidase subunit, gp91(phox) (Nrf2(-/-)//gp91(phox-/-)). Compared with Nrf2+/+ macrophages, LPS induced greater activation of TLR4 as evident by TLR4 surface trafficking and downstream recruitment of MyD88 and Toll/IL-1R domain-containing adaptor in Nrf2(-/-) macrophages that was diminished by ablation of gp91(phox). Similarly, phosphorylation of I kappa B and IFN regulatory factor 3 as well as cytokine expression was markedly higher in Nrf2(-/-) macrophages; whereas, it was similar in Nrf2(+/+) and Nrf2(-/-)//gp91(phox-/-). In vivo studies showed greater LPS-induced pulmonary inflammation in Nrf2(-/-) mice that was significantly reduced by ablation of gp91phox. Furthermore, LPS shock and polymicrobial sepsis induced early and greater mortality in Nrf2(-/-) mice; whereas, Nrf2(-/-)//gp91(phox-/-) showed prolong survival. Together, these results demonstrate that Nrf2 is essential for the regulation of NADPH oxidase-dependent ROS-mediated TLR4 activation and lethal innate immune response in sepsis. The Journal of Immunology, 2010, 185: 569-577.
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