TY - JOUR
T1 - Nrf2 is a critical modulator of the innate immune response in a model of uveitis
AU - Nagai, Norihiro
AU - Thimmulappa, Rajesh K.
AU - Cano, Marisol
AU - Fujihara, Masashi
AU - Izumi-Nagai, Kanako
AU - Kong, Xiaoni
AU - Sporn, Michael B.
AU - Kensler, Thomas W.
AU - Biswal, Shyam
AU - Handa, James T.
N1 - Funding Information:
This work is supported by Grant EY14005 (J.T.H.) and The Robert Bond Welch Professorship (J.T.H.); a Bausch and Laumb Fellowship Award (N.N.), the Keio University Medical Science Fund (N.N.), and The Uehara Memorial Foundation (N.N.); NIH HL081205 (S.B.), NIH/NHLBI SCCOR Grant P50HL084945 (S.B.), and a Clinical Innovator Award from FAMRI (S.B.); NIH Grant CA-78814 (M.S.) and a grant from Reata Pharmaceuticals (M.S.); and generous gifts from Ric and Sandy Forsythe, the Kwok family, the Merlau family, and Aleda Wright and from Research to Prevent Blindness to the Wilmer Eye Institute.
PY - 2009/8/1
Y1 - 2009/8/1
N2 - Uveitis is an inflammatory condition that can lead to blindness. It is therefore important to understand the pathophysiology against which to develop targeted therapy. Herein, we tested whether the oxidant-responsive transcription factor Nrf2 is involved in regulating the innate immune response and oxidative damage in the LPS uveitis model. As shown by dihydroethidium staining, intraperitoneally injected LPS increased reactive oxygen species in the retina and iris-ciliary body of Nrf2+/+ and Nrf2-/- mice. After LPS injection, ICAM-1, IL-6, TNF-α, COX-2, iNOS, and MCP-1 mRNAs were increased more in the retina and iris-ciliary body of Nrf2-/- than in those of Nrf2+/+ mice. NQO-1 and GCLM, two Nrf2-responsive antioxidant enzymes, had reduced expression in Nrf2+/+ retinas after LPS injection, but no change in expression in Nrf2-/- mice. The number of FITC-Con A-labeled leukocytes adherent to the retinal vascular endothelium increased after LPS treatment in both Nrf2+/+ and Nrf2-/- mice compared to control injections, with more adherent leukocytes in Nrf2-/- than in Nrf2+/+ mice. Pretreatment with the Nrf2 activator 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl)imidazole increased antioxidant gene expression in the retina, reduced inflammatory mediator expression, and reduced leukocyte adherence to retinal vasculature after LPS treatment in Nrf2+/+ mice, but had no effect on Nrf2-/- mice. Treatment targeting the Nrf2 pathway may be a new therapy for uveitis.
AB - Uveitis is an inflammatory condition that can lead to blindness. It is therefore important to understand the pathophysiology against which to develop targeted therapy. Herein, we tested whether the oxidant-responsive transcription factor Nrf2 is involved in regulating the innate immune response and oxidative damage in the LPS uveitis model. As shown by dihydroethidium staining, intraperitoneally injected LPS increased reactive oxygen species in the retina and iris-ciliary body of Nrf2+/+ and Nrf2-/- mice. After LPS injection, ICAM-1, IL-6, TNF-α, COX-2, iNOS, and MCP-1 mRNAs were increased more in the retina and iris-ciliary body of Nrf2-/- than in those of Nrf2+/+ mice. NQO-1 and GCLM, two Nrf2-responsive antioxidant enzymes, had reduced expression in Nrf2+/+ retinas after LPS injection, but no change in expression in Nrf2-/- mice. The number of FITC-Con A-labeled leukocytes adherent to the retinal vascular endothelium increased after LPS treatment in both Nrf2+/+ and Nrf2-/- mice compared to control injections, with more adherent leukocytes in Nrf2-/- than in Nrf2+/+ mice. Pretreatment with the Nrf2 activator 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl)imidazole increased antioxidant gene expression in the retina, reduced inflammatory mediator expression, and reduced leukocyte adherence to retinal vasculature after LPS treatment in Nrf2+/+ mice, but had no effect on Nrf2-/- mice. Treatment targeting the Nrf2 pathway may be a new therapy for uveitis.
KW - Adhesion molecules
KW - Cytokines
KW - Free radicals
KW - Lipopolysaccharide
KW - Nuclear factor erythroid-2 related factor 2
KW - Rodent
KW - Transcription factors
KW - Transgenic/knockout mice
KW - Triterpenoids
KW - Uveitis
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U2 - 10.1016/j.freeradbiomed.2009.04.033
DO - 10.1016/j.freeradbiomed.2009.04.033
M3 - Article
C2 - 19410644
AN - SCOPUS:67349238218
SN - 0891-5849
VL - 47
SP - 300
EP - 306
JO - Free Radical Biology and Medicine
JF - Free Radical Biology and Medicine
IS - 3
ER -