Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide.
Sepsis induced lethality is characterized by amplified host innate immune response. Nrf2, a bZIP transcription factor, regulates a battery of cellular antioxidative genes and maintains cellular redox homeostasis. This study demonstrates that increasing Nrf2 activity by a potent small molecule activator, CDDO-Im (1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole), protects from deregulation of lipopolysaccharide (LPS) induced innate immune response. In response to LPS stimuli, nrf2-deficient (nrf2 -/-) peritoneal neutrophils showed increased NADPH oxidase-dependent ROS generation, proinflammatory cytokines (Tnf-alpha and Il-6) and chemokines (Mip2 and Mcp-1) relative to wild-type (nrf2 +/+) cells. Pretreatment of peritoneal neutrophils with CDDO-Im induced antioxidative genes (Ho-1, Gclc, Gclm, and Nqo1) and attenuated LPS induced ROS generation as well as expression of proinflammatory cytokines exclusively in nrf2 +/+ neutrophils but not in nrf2 -/- cells. In corroboration with in vitro studies, pretreatment with CDDO-Im induced Nrf2-dependent antioxidative genes, attenuated LPS induced proinflammatory cytokine expression, and decreased mortality specifically in the nrf2 +/+ mice. In conclusion, the results suggest that Nrf2 is associated with oxidative regulation of LPS induced innate immune response in neutrophils. Activation of Nrf2-dependent compensatory antioxidative pathways by CDDO-Im protects from LPS induced inflammatory response and mortality.
Thimmulappa
Rajesh K
RK
Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Scollick
Catherine
C
Traore
Kassim
K
Yates
Melinda
M
Trush
Michael A
MA
Liby
Karen T
KT
Sporn
Michael B
MB
Yamamoto
Masayuki
M
Kensler
Thomas W
TW
Biswal
Shyam
S
D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D007093:Imidazoles / Q000633:toxicity; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000633:toxicity; D008168:Lung / Q000187:drug effects / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology*; D009828:Oleanolic Acid / Q000031:analogs & derivatives / Q000633:toxicity; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism
C472829:1-(2-cyano-3,12-dioxooleana-1,9-dien-28-oyl) imidazole; D018925:Chemokines; D016207:Cytokines; D007093:Imidazoles; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid