title: Calcitonin Gene-Related Peptide-Exposed Endothelial Cells Bias Antigen Presentation to CD4+ T Cells toward a Th17 Response.
abstract: Calcitonin gene-related peptide (CGRP) is a neuropeptide with well-established immunomodulatory functions. CGRP-containing nerves innervate dermal blood vessels and lymph nodes. We examined whether CGRP regulates the outcome of Ag presentation by Langerhans cells (LCs) to T cells through actions on microvascular endothelial cells (ECs). Exposure of primary murine dermal microvascular ECs (pDMECs) to CGRP followed by coculture with LCs, responsive CD4(+) T cells and Ag resulted in increased production of IL-6 and IL-17A accompanied by inhibition of IFN-γ, IL-4, and IL-22 compared with wells containing pDMECs treated with medium alone. Physical contact between ECs and LCs or T cells was not required for this effect and, except for IL-4, we demonstrated that IL-6 production by CGRP-treated pDMECs was involved in these effects. CD4(+) cells expressing cytoplasmic IL-17A were increased, whereas cells expressing cytoplasmic IFN-γ or IL-4 were decreased by the presence of CGRP-treated pDMECs. In addition, the level of retinoic acid receptor-related orphan receptor γt mRNA was significantly increased, whereas T-bet and GATA3 expression was inhibited. Immunization at the site of intradermally administered CGRP led to a similar bias in CD4(+) T cells from draining lymph node cells toward IL-17A and away from IFN-γ. Actions of nerve-derived CGRP on ECs may have important regulatory effects on the outcome of Ag presentation with consequences for the expression of inflammatory skin disorders involving Th17 cells.
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021;
authors.forename: Wanhong
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021;
authors.forename: Lori L
authors.initials: LL
authors.lastname: Stohl
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021;
authors.forename: Linghui
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Health Care Policy and Research, Weill Cornell Medical College, New York, NY 10065; and.
authors.forename: Xi K
authors.identifier: http://orcid.org/0000-0002-8942-439X
authors.initials: XK
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021;
authors.forename: Michela
authors.initials: M
authors.lastname: Manni
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065; and Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, New York, NY 10065.
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.affiliation: Department of Dermatology, Weill Cornell Medical College, New York, NY 10021; rdgranst@med.cornell.edu.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Granstein
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D015740:Calcitonin Gene-Related Peptide / Q000276:immunology*; D042783:Endothelial Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D007801:Langerhans Cells / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D058504:Th17 Cells / Q000276:immunology*; D014162:Transfection
chemical_list: D034741:RNA, Small Interfering; D015740:Calcitonin Gene-Related Peptide
references.citation: Cell. 1994 Jan 28;76(2):301-14
references.pmid: 7507411
references.citation: Lab Invest. 1994 Feb;70(2):217-27
references.pmid: 8139263
references.citation: J Immunol. 1995 Apr 1;154(7):3056-61
references.pmid: 7897198
references.citation: Proc Natl Acad Sci U S A. 1995 Aug 29;92(18):8323-7
references.pmid: 7667288
references.citation: J Immunol Methods. 1999 Feb 1;223(1):77-92
references.pmid: 10037236
references.citation: Cell Immunol. 2001 May 1;209(2):140-8
references.pmid: 11446746
references.citation: J Allergy Clin Immunol. 2001 Nov;108(5):688-96
references.pmid: 11692090
references.citation: Chin Med J (Engl). 2000 Aug;113(8):747-51
references.pmid: 11776062
references.citation: J Neuroimmunol. 1985 Nov;10(1):41-58
references.pmid: 3902887
references.citation: J Neurosci Res. 1987;18(1):28-36, 118-21
references.pmid: 3316680
references.citation: Immunol Today. 1989 Nov;10(11):370-5
references.pmid: 2514701
references.citation: Immunol Today. 1990 May;11(5):170-5
references.pmid: 2186751
references.citation: Cell. 1990 Aug 10;62(3):435-45
references.pmid: 2379237
references.citation: Science. 1990 Dec 21;250(4988):1720-3
references.pmid: 2125367
references.citation: Brain Behav Immun. 1991 Mar;5(1):29-40
references.pmid: 1712652
references.citation: Acta Oncol. 1991;30(4):509-17
references.pmid: 1713037
references.citation: J Immunol. 2004 Nov 15;173(10):6082-8
references.pmid: 15528344
references.citation: Int Immunol. 2005 Aug;17(8):1059-69
references.pmid: 16000327
references.citation: Dermatol Clin. 2005 Oct;23(4):681-94
references.pmid: 16112445
references.citation: J Neuroimmunol. 2006 Mar;172(1-2):38-58
references.pmid: 16375977
references.citation: Nature. 2007 Feb 8;445(7128):648-51
references.pmid: 17187052
references.citation: J Invest Dermatol. 2007 Oct;127(10):2357-67
references.pmid: 17495962
references.citation: Brain Behav Immun. 2008 Jan;22(1):80-8
references.pmid: 17716858
references.citation: Neuropsychopharmacology. 2008 Feb;33(3):566-73
references.pmid: 17460609
references.citation: J Immunol. 2008 Nov 1;181(9):6020-6
references.pmid: 18941191
references.citation: J Immunol. 2009 May 1;182(9):5836-45
references.pmid: 19380832
references.citation: J Mol Med (Berl). 2009 May;87(5):523-36
references.pmid: 19330474
references.citation: J Neuroimmunol. 2002 Feb;123(1-2):83-90
references.pmid: 11880153
references.citation: J Immunol. 2002 Jun 15;168(12):6128-35
references.pmid: 12055224
references.citation: Cleve Clin J Med. 2002;69 Suppl 2:SII45-9
references.pmid: 12086264
references.citation: Stress. 2003 Mar;6(1):59-62
references.pmid: 12637208
references.citation: Crit Care Med. 2003 Apr;31(4 Suppl):S221-30
references.pmid: 12682444
references.citation: J Neuroimmunol. 2003 Jul;140(1-2):28-40
references.pmid: 12864969
references.citation: Eur J Immunol. 2003 Nov;33(11):3070-9
references.pmid: 14579275
references.citation: J Immunol. 2004 Mar 1;172(5):2731-8
references.pmid: 14978070
references.citation: Eur J Pharmacol. 2004 Oct 1;500(1-3):315-30
references.pmid: 15464043
references.citation: Arch Dermatol. 1971 Aug;104(2):220-1
references.pmid: 5093177
references.citation: J Anat. 1973 Apr;114(Pt 3):389-405
references.pmid: 4736747
references.citation: J Immunol. 1978 Nov;121(5):2005-13
references.pmid: 81860
references.citation: Experientia. 1983 Sep 15;39(9):1018-20
references.pmid: 6193004
references.citation: Proc Natl Acad Sci U S A. 1984 Aug;81(15):4917-21
references.pmid: 6431411
references.citation: Histochemistry. 1984;81(2):111-4
references.pmid: 6386754
references.citation: Immunobiology. 1984 Dec;168(3-5):285-300
references.pmid: 6397423
references.citation: Immunobiology. 1984 Dec;168(3-5):483-94
references.pmid: 6397428
references.citation: Regul Pept. 1985 Mar;10(2-3):189-97
references.pmid: 3922013
references.citation: Proc Natl Acad Sci U S A. 2009 Dec 22;106(51):21795-800
references.pmid: 19996179
references.citation: Arthritis Res Ther. 2009;11(6):257
references.pmid: 20053303
references.citation: J Invest Dermatol. 2010 May;130(5):1373-83
references.pmid: 20032993
references.citation: Immunol Rev. 2010 Nov;238(1):247-62
references.pmid: 20969597
references.citation: G Ital Dermatol Venereol. 2011 Feb;146(1):17-30
references.pmid: 21317854
references.citation: Immunology. 2011 Apr;132(4):540-8
references.pmid: 21214545
references.citation: Brain Behav Immun. 2011 May;25(4):787-99
references.pmid: 21334428
references.citation: J Invest Dermatol. 2011 Jul;131(7):1530-8
references.pmid: 21471984
references.citation: Immunity. 2011 Aug 26;35(2):260-72
references.pmid: 21782478
references.citation: Clin Rev Allergy Immunol. 2011 Dec;41(3):259-66
references.pmid: 21181506
references.citation: Eur J Immunol. 2012 Apr;42(4):901-11
references.pmid: 22531916
references.citation: PLoS One. 2012;7(4):e33069
references.pmid: 22558071
references.citation: Cell Mol Immunol. 2012 Jul;9(4):302-9
references.pmid: 22705915
references.citation: Immunol Rev. 2013 Mar;252(1):116-32
references.pmid: 23405899
references.citation: Nat Immunol. 2013 Jun;14(6):584-92
references.pmid: 23624556
references.citation: Annu Rev Immunol. 2014;32:227-55
references.pmid: 24655295
references.citation: Nature. 2014 Jun 5;510(7503):157-61
references.pmid: 24759321
references.citation: J Am Acad Dermatol. 2014 Jul;71(1):141-50
references.pmid: 24655820
references.citation: BioDrugs. 2014 Dec;28(6):487-97
references.pmid: 24890029
references.citation: J Dermatolog Treat. 2015 Feb;26(1):32-6
references.pmid: 24552447
references.citation: J Clin Invest. 2012 Jun;122(6):2252-6
references.pmid: 22546855
references.citation: Int J Immunopharmacol. 1992 Apr;14(3):329-44
references.pmid: 1319962
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):6065-9
references.pmid: 1385868
references.citation: J Invest Dermatol. 1993 Jan;100(1):111S-115S
references.pmid: 8423379
references.citation: J Am Acad Dermatol. 1993 Mar;28(3):488-9
references.pmid: 7680359
references.citation: Nature. 1993 May 13;363(6425):159-63
references.pmid: 8483499
references.citation: J Immunol. 1993 Nov 15;151(10):5239-50
references.pmid: 7693807