Disruption of the transcription factor Nrf2 promotes pro-oxidative dendritic cells that stimulate Th2-like immunoresponsiveness upon activation by ambient particulate matter.
Oxidative stress is important in dendritic cell (DC) activation. Environmental particulate matter (PM) directs pro-oxidant activities that may alter DC function. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive transcription factor that regulates expression of antioxidant and detoxification genes. Oxidative stress and defective antioxidant responses may contribute to the exacerbations of asthma. We hypothesized that PM would impart differential responses by Nrf2 wild-type DCs as compared with Nrf2(-/-) DCs. We found that the deletion of Nrf2 affected important constitutive functions of both bone marrow-derived and highly purified myeloid lung DCs such as the secretion of inflammatory cytokines and their ability to take up exogenous Ag. Stimulation of Nrf2(-/-) DCs with PM augmented oxidative stress and cytokine production as compared with resting or Nrf2(+/+) DCs. This was associated with the enhanced induction of Nrf2-regulated antioxidant genes. In contrast to Nrf2(+/+) DCs, coincubation of Nrf2(-/-) DCs with PM and the antioxidant N-acetyl cysteine attenuated PM-induced up-regulation of CD80 and CD86. Our studies indicate a previously underappreciated role of Nrf2 in innate immunity and suggest that deficiency in Nrf2-dependent pathways may be involved in susceptibility to the adverse health effects of air pollution in part by promoting Th2 cytokine responses in the absence of functional Nrf2. Moreover, our studies have uncovered a hierarchal response to oxidative stress in terms of costimulatory molecule expression and cytokine secretion in DCs and suggest an important role of heightened oxidative stress in proallergic Th2-mediated immune responses orchestrated by DCs.
Williams
Marc A
MA
Division of Pulmonary and Critical Care Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. marc_williams@urmc.rochester.edu
Rangasamy
Tirumalai
T
Bauer
Stephen M
SM
Killedar
Smruti
S
Karp
Matthew
M
Kensler
Thomas W
TW
Yamamoto
Masayuki
M
Breysse
Patrick
P
Biswal
Shyam
S
Georas
Steve N
SN
D000818:Animals; D015142:Baltimore; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics*; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology*; D052638:Particulate Matter / Q000633:toxicity*; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D052638:Particulate Matter
Nat Immunol. 2000 Sep;1(3):199-205
10973276
Nat Immunol. 2000 Oct;1(4):311-6
11017102
J Allergy Clin Immunol. 2001 May;107(5):863-70
11344354
Cell. 2001 Aug 10;106(3):255-8
11509172
Free Radic Res. 2001 Dec;35(6):681-91
11811521
Free Radic Biol Med. 2002 Mar 1;32(5):377-85
11864777
J Allergy Clin Immunol. 2002 Sep;110(3):443-9
12209092
Eur J Immunol. 2002 Oct;32(10):2866-73
12355439
Am J Respir Cell Mol Biol. 2002 Oct;27(4):413-8
12356574
J Hematother Stem Cell Res. 2002 Oct;11(5):829-47
12427289
Pharmacology. 1978;16(6):314-20
674350
Science. 2003 Jul 4;301(5629):94-6
12843393
Altern Med Rev. 2003 Aug;8(3):223-46
12946237
J Immunol. 2003 Sep 15;171(6):3010-8
12960326
Trends Biochem Sci. 2003 Sep;28(9):488-94
13678960
Blood. 2003 Nov 15;102(10):3668-74
12855564
Curr Opin Immunol. 2003 Dec;15(6):620-6
14630194
Blood. 2004 Feb 1;103(3):761-6
14525760
J Immunol. 2004 Mar 15;172(6):3808-13
15004186
Cancer Immunol Immunother. 2004 Jun;53(6):543-50
14666382
J Immunol. 2004 Sep 1;173(5):3467-81
15322212
Nat Med. 2004 Oct;10(10):1095-103
15378055
J Immunol. 2000 Aug 15;165(4):2214-21
10925309
J Clin Invest. 2000 Aug;106(4):551-9
10953030
J Immunol. 2000 Sep 15;165(6):3393-401
10975858
J Exp Med. 1990 Dec 1;172(6):1861-4
1701824
Clin Exp Allergy. 1992 Dec;22(12):1107-14
1486539
Science. 1993 Apr 23;260(5107):547-9
8097338
J Allergy Clin Immunol. 1994 Feb;93(2):476-83
8120275
Br J Haematol. 1995 May;90(1):31-40
7540415
Biochem Biophys Res Commun. 1997 Jul 18;236(2):313-22
9240432
J Infect Dis. 1998 Jan;177(1):107-15
9419177
J Immunol. 1998 Feb 1;160(3):1224-32
9570538
Free Radic Biol Med. 1999 Jan;26(1-2):232-8
9890657
J Immunol. 1999 Mar 1;162(5):2569-74
10072497
J Clin Invest. 2004 Nov;114(9):1248-59
15520857
J Immunol. 2005 Feb 15;174(4):2412-9
15699178
Nat Immunol. 2005 Mar;6(3):223-6
15716966
J Invest Dermatol. 2005 Mar;124(3):579-86
15737199
J Exp Med. 2005 Mar 21;201(6):981-91
15781587
J Exp Med. 2005 Jul 4;202(1):47-59
15998787
J Toxicol Environ Health A. 2005 Jul 9-23;68(13-14):1071-92
16024489
Blood. 2005 Sep 1;106(5):1694-702
15920011
Am J Respir Crit Care Med. 2005 Sep 1;172(5):530-51
15879415
J Allergy Clin Immunol. 2005 Oct;116(4):906-9
16210068
Cytokine. 2005 Nov 3;32(3-4):178-85
16290175
Am J Respir Crit Care Med. 2006 Mar 15;173(6):667-72
16424447
Immunity. 2006 Mar;24(3):241-3
16546091
FASEB J. 2006 Apr;20(6):776-8
16473885
J Clin Invest. 2006 Apr;116(4):984-95
16585964
J Hepatol. 2006 Jun;44(6):1033-9
16458992
J Immunol. 2006 Jun 15;176(12):7431-7
16751388
J Allergy Clin Immunol. 2006 Aug;118(2):455-65
16890772
J Immunol. 2006 Nov 1;177(9):6460-70
17056578
J Biol Chem. 2006 Nov 3;281(44):33761-72
16950787
Leuk Lymphoma. 2006 Oct;47(10):2224-33
17071499
Drug Metab Rev. 2006;38(4):769-89
17145701
Trends Immunol. 2007 Jan;28(1):33-8
17126601
J Immunol. 2007 Jan 15;178(2):908-17
17202352
Annu Rev Pharmacol Toxicol. 2007;47:89-116
16968214
J Immunol. 2007 Feb 1;178(3):1948-59
17237446
J Allergy Clin Immunol. 2007 Feb;119(2):488-97
17187851
J Allergy Clin Immunol. 2007 Mar;119(3):680-6
17336618
Eur Cytokine Netw. 2006 Dec;17(4):224-52
17353157
Adv Immunol. 2007;93:265-78
17383544
J Allergy Clin Immunol. 2007 May;119(5):1225-33
17335885
Am J Respir Cell Mol Biol. 2007 Jun;36(6):669-77
17272826
Curr Opin Pharmacol. 2007 Jun;7(3):279-82
17475560
Am J Respir Cell Mol Biol. 2007 Jul;37(1):3-8
17413030
Nature. 2006 Jul 6;442(7098):39-44
16823444
Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L260-9
12388339
Am J Respir Crit Care Med. 2003 Feb 1;167(3):431-7
12554628
Br J Pharmacol. 2003 Jun;139(3):634-40
12788823
Am J Physiol Lung Cell Mol Physiol. 2000 Dec;279(6):L1029-37
11076792
Trends Cell Biol. 2000 Dec;10(12):542-50
11121747