TY - JOUR
T1 - Kallikrein 7 Promotes Atopic Dermatitis-Associated Itch Independently of Skin Inflammation
AU - Guo, Changxiong J.
AU - Mack, Madison R.
AU - Oetjen, Landon K.
AU - Trier, Anna M.
AU - Council, Martha L.
AU - Pavel, Ana B.
AU - Guttman-Yassky, Emma
AU - Kim, Brian S.
AU - Liu, Qin
N1 - Funding Information:
Research in the Kim Lab is supported by the Doris Duke Charitable Foundation, Celgene Corporation, LEO Pharma, and the National Institute of Arthritis Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [NIH (K08AR065577 and R01AR070116)]. MRM was supported by the NIH National Institute of Allergy and Infectious Diseases T325T32AI00716340. AMT is supported by the NIH National Heart, Lung, and Blood Institute T32 HL007317. The Kim Lab has also been generously supported by donations from Anabeth and John Weil and Carole Kroeger. Research in the Liu Lab is supported by the NIH (R01AI125743), Brain Research Foundation Fay / Frank Seed Grant, and Pew Scholar Award to QL. The Klk7tm1(KOMP)Vlcg mouse strain used for this research project was generated by the trans-NIH Knock-Out Mouse Project and obtained from the Knock-Out Mouse Project Repository (www.komp.org). NIH grants to Velocigene at Regeneron Inc (U01HG004085) and the CSD Consortium (U01HG004080) funded the generation of gene-targeted embryonic stem cells for 8,500 genes, including Klk7, in the Knock-Out Mouse Project Program and archived and distributed by the Knock-Out Mouse Project Repository at UC Davis and CHORI (U42RR024244). Conceptualization: CJG, MRM, QL, BSK; Data curation: MRM; Formal Analysis: CJG, MRM, ABP; Funding Acquisition: QL, BSK, EG; Investigation: CJG, MRM, ABP, LKO, AMT; Methodology: CJG, MRM, QL, BSK; Resources: MRM, BSK, MLC, EG; Supervision: QL and BSK; Validation: MRM, BSK, ABP, EG; Visualization: CJG and MRM; Writing – Original Draft: CJG, MRM, QL, BSK; Writing – Review & Editing: CJG, MRM, AMT, QL, BSK, ABP, and EG.
Funding Information:
Research in the Kim Lab is supported by the Doris Duke Charitable Foundation , Celgene Corporation , LEO Pharma , and the National Institute of Arthritis Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH) [NIH ( K08AR065577 and R01AR070116 )]. MRM was supported by the NIH National Institute of Allergy and Infectious Diseases T325T32AI00716340 . AMT is supported by the NIH National Heart, Lung, and Blood Institute T32 HL007317 . The Kim Lab has also been generously supported by donations from Anabeth and John Weil and Carole Kroeger. Research in the Liu Lab is supported by the NIH ( R01AI125743 ), Brain Research Foundation Fay / Frank Seed Grant , and Pew Scholar Award to QL.
Funding Information:
The Klk7 tm1(KOMP)Vlcg mouse strain used for this research project was generated by the trans-NIH Knock-Out Mouse Project and obtained from the Knock-Out Mouse Project Repository ( www.komp.org ). NIH grants to Velocigene at Regeneron Inc ( U01HG004085 ) and the CSD Consortium ( U01HG004080 ) funded the generation of gene-targeted embryonic stem cells for 8,500 genes, including Klk7, in the Knock-Out Mouse Project Program and archived and distributed by the Knock-Out Mouse Project Repository at UC Davis and CHORI (U42RR024244).
Publisher Copyright:
© 2019 The Authors
PY - 2020/6
Y1 - 2020/6
N2 - Atopic dermatitis (AD) is a highly prevalent, itchy inflammatory skin disorder that is thought to arise from a combination of skin barrier defect and immune dysregulation. Kallikreins (KLK), a family of serine proteases with a diverse array of homeostatic functions, including skin desquamation and innate immunity, are hypothesized to contribute to AD pathogenesis. However, their precise role in AD has not been clearly defined. In this study, RNA sequencing analyses identified KLK7 as the most abundant and differentially expressed KLK in both human AD and murine AD-like skin. Further, in mice, Klk7 expression was localized to the epidermis in both steady state and inflammation. Unexpectedly, KLK7 was dispensable for the development of AD-associated skin inflammation. Instead, KLK7 was selectively required for AD-associated chronic itch. Even without the alleviation of skin inflammation, KLK7-deficient mice exhibited significantly attenuated scratching, compared with littermate controls, after AD-like disease induction. Collectively, our findings indicate that KLK7 promotes AD-associated itch independently from skin inflammation and reveal a previously unrecognized epidermal-neural mechanism of AD associated itch.
AB - Atopic dermatitis (AD) is a highly prevalent, itchy inflammatory skin disorder that is thought to arise from a combination of skin barrier defect and immune dysregulation. Kallikreins (KLK), a family of serine proteases with a diverse array of homeostatic functions, including skin desquamation and innate immunity, are hypothesized to contribute to AD pathogenesis. However, their precise role in AD has not been clearly defined. In this study, RNA sequencing analyses identified KLK7 as the most abundant and differentially expressed KLK in both human AD and murine AD-like skin. Further, in mice, Klk7 expression was localized to the epidermis in both steady state and inflammation. Unexpectedly, KLK7 was dispensable for the development of AD-associated skin inflammation. Instead, KLK7 was selectively required for AD-associated chronic itch. Even without the alleviation of skin inflammation, KLK7-deficient mice exhibited significantly attenuated scratching, compared with littermate controls, after AD-like disease induction. Collectively, our findings indicate that KLK7 promotes AD-associated itch independently from skin inflammation and reveal a previously unrecognized epidermal-neural mechanism of AD associated itch.
UR - http://www.scopus.com/inward/record.url?scp=85078889010&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2019.10.022
DO - 10.1016/j.jid.2019.10.022
M3 - Article
C2 - 31883963
AN - SCOPUS:85078889010
SN - 0022-202X
VL - 140
SP - 1244-1252.e4
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 6
ER -