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NLRP3 Inhibition Ameliorates Severe Cutaneous Autoimmune Manifestations in a Mouse Model of Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy-Like Disease.

Authors
  • Zhu, Feng1
  • Willette-Brown, Jami1
  • Zhang, Jian2
  • Ferre, Elise M N3
  • Sun, Zhonghe4
  • Wu, Xiaolin4
  • Lionakis, Michail S3
  • Hu, Yinling5
  • 1 Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA.
  • 2 Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA; Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China; National Clinical Research Center for Eye Diseases, Shanghai, China; Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China. , (China)
  • 3 Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA.
  • 4 Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA.
  • 5 Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, Maryland, USA. Electronic address: [email protected]
Type
Published Article
Journal
Journal of Investigative Dermatology
Publisher
Elsevier
Publication Date
Jun 01, 2021
Volume
141
Issue
6
Pages
1404–1415
Identifiers
DOI: 10.1016/j.jid.2020.10.016
PMID: 33188780
Source
Medline
Language
English
License
Unknown

Abstract

Patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy show diverse endocrine and nonendocrine manifestations initiated by self-reactive T cells because of AIRE mutation-induced defective central tolerance. A large number of American patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy suffer from early-onset cutaneous inflammatory lesions accompanied by an infiltration of T cells and myeloid cells. The role of myeloid cells in this setting remains to be fully investigated. In this study, we characterize the autoinflammatory phenotypes in the skin of both autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-like kinase-dead Ikkα knockin mice and patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. We found a marked infiltration of autoreactive CD4 T cells, macrophages, and neutrophils; elevated uric acid; and increased NLRP3, a major inflammasome component. Depleting autoreactive CD4 T cells or ablating Ccl2/Cxcr2 genes significantly attenuated the inflammasome activity, inflammation, and skin phenotypes in kinase-dead Ikkα knockin mice. Importantly, treatment with an NLRP3 inhibitor reduced skin phenotypes and decreased infiltration of CD4 T cells, macrophages, and neutrophils. These results suggest that increased myeloid cell infiltration contributes to autoreactive CD4 T cell-mediated skin autoinflammation. Thus, our findings reveal that the combined infiltration of macrophages and neutrophils is required for autoreactive CD4 T cell-mediated skin disease pathogenesis and that the NLRP3-dependent inflammasome is a potential therapeutic target for the cutaneous manifestations of autoimmune diseases. Published by Elsevier Inc.

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