@article{b0e83ab533304287938f8404ea548812,
title = "Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1α release",
abstract = "Background: Atopic dermatitis (AD) is associated with epidermal barrier defects, dysbiosis, and skin injury caused by scratching. In particular, the barrier-defective epidermis in patients with AD with loss-of-function filaggrin mutations has increased IL-1α and IL-1β levels, but the mechanisms by which IL-1α IL-1β or both are induced and whether they contribute to the aberrant skin inflammation in patients with AD is unknown. Objective: We sought to determine the mechanisms through which skin injury, dysbiosis, and increased epidermal IL-1α and IL-1β levels contribute to development of skin inflammation in a mouse model of injury-induced skin inflammation in filaggrin-deficient mice without the matted mutation (ft/ft mice). Methods: Skin injury of wild-type, ft/ft, and myeloid differentiation primary response gene–88–deficient ft/ft mice was performed, and ensuing skin inflammation was evaluated by using digital photography, histologic analysis, and flow cytometry. IL-1α and IL-1β protein expression was measured by means of ELISA and visualized by using immunofluorescence and immunoelectron microscopy. Composition of the skin microbiome was determined by using 16S rDNA sequencing. Results: Skin injury of ft/ft mice induced chronic skin inflammation involving dysbiosis-driven intracellular IL-1α release from keratinocytes. IL-1α was necessary and sufficient for skin inflammation in vivo and secreted from keratinocytes by various stimuli in vitro. Topical antibiotics or cohousing of ft/ft mice with unaffected wild-type mice to alter or intermix skin microbiota, respectively, resolved the skin inflammation and restored keratinocyte intracellular IL-1α localization. Conclusions: Taken together, skin injury, dysbiosis, and filaggrin deficiency triggered keratinocyte intracellular IL-1α release that was sufficient to drive chronic skin inflammation, which has implications for AD pathogenesis and potential therapeutic targets.",
keywords = "IL-1α, Skin, atopic dermatitis, filaggrin, inflammation, keratinocytes",
author = "Archer, {Nathan K.} and Jo, {Jay Hyun} and Lee, {Steven K.} and Dongwon Kim and Barbara Smith and Ortines, {Roger V.} and Yu Wang and Marchitto, {Mark C.} and Advaitaa Ravipati and Cai, {Shuting S.} and Dillen, {Carly A.} and Haiyun Liu and Miller, {Robert J.} and Ashbaugh, {Alyssa G.} and Uppal, {Angad S.} and Oyoshi, {Michiko K.} and Nidhi Malhotra and Sabine Hoff and Garza, {Luis A.} and Kong, {Heidi H.} and Segre, {Julia A.} and Geha, {Raif S.} and Miller, {Lloyd S.}",
note = "Funding Information: Images of immunofluorescent-stained skin sections (see above) were captured on a laser scanning confocal microscope (710 NLO; Zeiss, Oberkochen, Germany) with a ×40/1.1W LD C-Apo objective (NIH grant S10 RR024550 [Institute: Research Resources]). Images for analysis were captured on a Zeiss LSM 800 with a PlanApo 20X (NA 0.8) dry objective. Analysis was performed with Volocity software (V6.3; PerkinElmer, Waltham, Mass) by using the Pearson coefficient for colocalization with a minimum of 5 images analyzed per sample.26 Regions of interest were manually selected to include only the epidermis and associated nuclei. Funding Information: Supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (grant no. R01AR069502 ; to L.S.M., grant no. R01AR073665; to L.S.M., and grant no. K01AR073924; to N.K.A.), the National Institute of Allergy and Infectious Diseases (grant no. R21AI126896 ; to L.S.M.), and a contract/grant from the Atopic Dermatitis Research Network ( U19AI117673-01 ; to R.S.G. and L.S.M.), and the Division of Intramural Research ( ZIAHG000180-17 and ZIABC011558-04 ; to H.H.K. and J.A.S.) from the US National Institutes of Health , Department of Health and Human Services . Supported also by the Food Allergy Research & Education (FARE), Inc (to M.K.O.), the HOPE APFED/ARTrust TM Pilot Grant (to M.K.O.), the William F. Milton Fund, the Harvard Catalyst Clinical and Translational Research Center (NCATS grant no. 8UL 1TR000170 ; to M.K.O.), and the Boston Children's Hospital Pediatric Associates Award (to M.K.O.). Funding Information: Supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (grant no. R01AR069502; to L.S.M., grant no. R01AR073665; to L.S.M., and grant no. K01AR073924; to N.K.A.), the National Institute of Allergy and Infectious Diseases (grant no. R21AI126896; to L.S.M.), and a contract/grant from the Atopic Dermatitis Research Network (U19AI117673-01; to R.S.G. and L.S.M.), and the Division of Intramural Research (ZIAHG000180-17 and ZIABC011558-04; to H.H.K. and J.A.S.) from the US National Institutes of Health, Department of Health and Human Services. Supported also by the Food Allergy Research & Education (FARE), Inc (to M.K.O.), the HOPE APFED/ARTrust TM Pilot Grant (to M.K.O.), the William F. Milton Fund, the Harvard Catalyst Clinical and Translational Research Center (NCATS grant no. 8UL 1TR000170; to M.K.O.), and the Boston Children's Hospital Pediatric Associates Award (to M.K.O.).Disclosure of potential conflict of interest: L. S. Miller has received grant support from MedImmune, Pfizer, Regeneron Pharmaceuticals, Moderna Therapeutics, and Boehringer Ingelheim; is on the scientific advisory board for Integrated Biotherapeutics; and is a shareholder of Noveome Biotherapeutics, which are all unrelated to the work reported in this article. The rest of the authors declare that they have no relevant conflicts of interest.Images of immunofluorescent-stained skin sections (see above) were captured on a laser scanning confocal microscope (710 NLO; Zeiss, Oberkochen, Germany) with a ×40/1.1W LD C-Apo objective (NIH grant S10 RR024550 [Institute: Research Resources]). Images for analysis were captured on a Zeiss LSM 800 with a PlanApo 20X (NA 0.8) dry objective. Analysis was performed with Volocity software (V6.3; PerkinElmer, Waltham, Mass) by using the Pearson coefficient for colocalization with a minimum of 5 images analyzed per sample.26 Regions of interest were manually selected to include only the epidermis and associated nuclei. Supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (grant no. R01AR069502; to L.S.M., grant no. R01AR073665; to L.S.M., and grant no. K01AR073924; to N.K.A.), the National Institute of Allergy and Infectious Diseases (grant no. R21AI126896; to L.S.M.), and a contract/grant from the Atopic Dermatitis Research Network (U19AI117673-01; to R.S.G. and L.S.M.), and the Division of Intramural Research (ZIAHG000180-17 and ZIABC011558-04; to H.H.K. and J.A.S.) from the US National Institutes of Health, Department of Health and Human Services. Supported also by the Food Allergy Research & Education (FARE), Inc (to M.K.O.), the HOPE APFED/ARTrust TM Pilot Grant (to M.K.O.), the William F. Milton Fund, the Harvard Catalyst Clinical and Translational Research Center (NCATS grant no. 8UL 1TR000170; to M.K.O.), and the Boston Children's Hospital Pediatric Associates Award (to M.K.O.). Disclosure of potential conflict of interest: L. S. Miller has received grant support from MedImmune, Pfizer, Regeneron Pharmaceuticals, Moderna Therapeutics, and Boehringer Ingelheim; is on the scientific advisory board for Integrated Biotherapeutics; and is a shareholder of Noveome Biotherapeutics, which are all unrelated to the work reported in this article. The rest of the authors declare that they have no relevant conflicts of interest. We dedicate this work to the memory of Dr Mark E. Shirtliff, who provided invaluable intellectual support as a mentor and colleague. We thank the Johns Hopkins University School of Medicine Microscope Facility for use of the Philips CM120 TEM device. Supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (grant no. R01AR069502; to L.S.M., grant no. R01AR073665; to L.S.M., and grant no. K01AR073924; to N.K.A.), the National Institute of Allergy and Infectious Diseases (grant no. R21AI126896; to L.S.M.), and a contract/grant from the Atopic Dermatitis Research Network (U19AI117673-01; to R.S.G. and L.S.M.), and the Division of Intramural Research (ZIAHG000180-17 and ZIABC011558-04; to H.H.K. and J.A.S.) from the US National Institutes of Health, Department of Health and Human Services. Supported also by the Food Allergy Research & Education (FARE), Inc (to M.K.O.), the HOPE APFED/ARTrust TM Pilot Grant (to M.K.O.), the William F. Milton Fund, the Harvard Catalyst Clinical and Translational Research Center (NCATS grant no. 8UL 1TR000170; to M.K.O.), and the Boston Children's Hospital Pediatric Associates Award (to M.K.O.). Disclosure of potential conflict of interest: L. S. Miller has received grant support from MedImmune, Pfizer, Regeneron Pharmaceuticals, Moderna Therapeutics, and Boehringer Ingelheim; is on the scientific advisory board for Integrated Biotherapeutics; and is a shareholder of Noveome Biotherapeutics, which are all unrelated to the work reported in this article. The rest of the authors declare that they have no relevant conflicts of interest. Publisher Copyright: {\textcopyright} 2018 American Academy of Allergy, Asthma & Immunology",
year = "2019",
month = apr,
doi = "10.1016/j.jaci.2018.08.042",
language = "English (US)",
volume = "143",
pages = "1426--1443.e6",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
number = "4",
}