Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease.
Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, because topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.
University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA.
Jillian M
JM
Richmond
Sanofi-Genzyme, Framingham, Massachusetts, USA.
Dinesh S
DS
Bangari
University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA.
Kingsley I
KI
Essien
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Sharif D
SD
Currimbhoy
The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Department of Medical Biology 1G Royal Parade, Victoria, Australia.
Joanna R
JR
Groom
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Amit G
AG
Pandya
Sanofi-Genzyme, Framingham, Massachusetts, USA.
Michele E
ME
Youd
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Andrew D
AD
Luster
University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA. Electronic address: john.harris@umassmed.edu.
John E
JE
Harris
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D054357:Chemokine CXCL10 / Q000032:analysis / Q000502:physiology; D054370:Chemokine CXCL9 / Q000032:analysis / Q000502:physiology; D018925:Chemokines / Q000502:physiology*; D004817:Epidermis / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology; D015603:Keratinocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000502:physiology*; D014820:Vitiligo / Q000188:drug therapy / Q000276:immunology*
D015415:Biomarkers; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D018925:Chemokines; C074302:keratinocyte-derived chemokines; D007371:Interferon-gamma
J Interferon Cytokine Res. 2000 Jun;20(6):565-76
10888113
Immunity. 2000 Jun;12(6):677-86
10894167
Nat Rev Immunol. 2014 May;14(5):289-301
24722477
Nature. 2012 Nov 15;491(7424):463-7
23075848
Microcirculation. 2003 Jun;10(3-4):313-23
12851648
Cell. 2013 Feb 14;152(4):743-54
23415224
Dev Biol. 2011 May 1;353(1):1-9
21334322
Science. 2014 Oct 3;346(6205):93-8
25170048
J Invest Dermatol. 2015 Apr;135(4):1080-1088
25521459
Immunol Cell Biol. 2011 Feb;89(2):207-15
21221121
Sci Transl Med. 2014 Feb 12;6(223):223ra23
24523323
Annu Rev Immunol. 2014;32:227-55
24655295
Int J Mol Med. 1999 May;3(5):477-84
10202178
Br J Dermatol. 2016 Jun;174(6):1318-26
26801009
J Immunol. 2003 Jul 15;171(2):1078-84
12847282
Science. 2012 Jun 8;336(6086):1317-21
22679098
Cell. 1993 Feb 12;72(3):337-48
8381716
Cell. 2016 Jun 16;165(7):1672-1685
27315481
Nat Immunol. 2013 May;14(5):509-13
23542740
Opt Express. 1998 Oct 26;3(9):339-50
19384379
J Virol. 2014 Feb;88(3):1582-90
24257594
Inflamm Bowel Dis. 2008 Jul;14(7):1000-11
18452220
J Biol Chem. 2004 Jul 16;279(29):30219-27
15150261
Nat Rev Dis Primers. 2015 Jun 04;1:15011
27189851
J Invest Dermatol. 2012 Jul;132(7):1869-76
22297636
J Invest Dermatol. 2015 Dec;135(12):3105-3114
26322948
Immunity. 2005 Dec;23(6):611-20
16356859
Immunity. 2012 Dec 14;37(6):1091-103
23123063
Lancet. 2015 Jul 4;386(9988):74-84
25596811
Annu Rev Immunol. 2014;32:513-45
24555472
J Dermatol Sci. 2002 Apr;28(3):234-41
11912011