Disruption of the endopeptidase ADAM10-Notch signaling axis leads to skin dysbiosis and innate lymphoid cell-mediated hair follicle destruction
Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and...
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| Vydáno v: | Immunity (Cambridge, Mass.) Ročník 54; číslo 10; s. 2321 |
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| Médium: | Journal Article |
| Jazyk: | angličtina |
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United States
12.10.2021
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| ISSN: | 1097-4180, 1097-4180 |
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| Abstract | Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting β-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation. |
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| AbstractList | Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting β-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting β-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation. Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting β-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation. |
| Author | Liang, Hai Sakamoto, Keiko Horiuchi, Keisuke Jin, Seon-Pil Voisin, Benjamin Nadella, Vinod Nagao, Keisuke Kobayashi, Tetsuro Huang, Xin Jo, Jay-Hyun Goel, Shubham Deming, Clay Segre, Julia A Kong, Heidi H Kim, Doyoung |
| Author_xml | – sequence: 1 givenname: Keiko surname: Sakamoto fullname: Sakamoto, Keiko organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 2 givenname: Seon-Pil surname: Jin fullname: Jin, Seon-Pil organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 3 givenname: Shubham surname: Goel fullname: Goel, Shubham organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 4 givenname: Jay-Hyun surname: Jo fullname: Jo, Jay-Hyun organization: Cutaneous Microbiome and Inflammation Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 5 givenname: Benjamin surname: Voisin fullname: Voisin, Benjamin organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 6 givenname: Doyoung surname: Kim fullname: Kim, Doyoung organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 7 givenname: Vinod surname: Nadella fullname: Nadella, Vinod organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 8 givenname: Hai surname: Liang fullname: Liang, Hai organization: Cutaneous Microbiome and Inflammation Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 9 givenname: Tetsuro surname: Kobayashi fullname: Kobayashi, Tetsuro organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 10 givenname: Xin surname: Huang fullname: Huang, Xin organization: Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 11 givenname: Clay surname: Deming fullname: Deming, Clay organization: Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 12 givenname: Keisuke surname: Horiuchi fullname: Horiuchi, Keisuke organization: Department of Orthopedic Surgery, National Defense Medical College, Saitama 359-8513, Japan – sequence: 13 givenname: Julia A surname: Segre fullname: Segre, Julia A organization: Microbial Genomics Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 14 givenname: Heidi H surname: Kong fullname: Kong, Heidi H organization: Cutaneous Microbiome and Inflammation Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA – sequence: 15 givenname: Keisuke surname: Nagao fullname: Nagao, Keisuke email: keisuke.nagao@nih.gov organization: Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: keisuke.nagao@nih.gov |
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| Keywords | pyroptosis hair follicles alopecia Notch ADAM10 skin microbiota innate lymphoid cells caspase cicatricial alopecia dysbiosis |
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| SubjectTerms | ADAM10 Protein - immunology Alopecia - immunology Alopecia - pathology Amyloid Precursor Protein Secretases - immunology Animals Corynebacterium Dysbiosis - immunology Dysbiosis - pathology Female Hair Follicle - immunology Hair Follicle - pathology Immunity, Innate Inflammation - immunology Inflammation - metabolism Inflammation - pathology Lymphocytes - immunology Membrane Proteins - immunology Mice Receptors, Notch - immunology Signal Transduction - immunology Skin - immunology Skin - microbiology Skin - pathology |
| Title | Disruption of the endopeptidase ADAM10-Notch signaling axis leads to skin dysbiosis and innate lymphoid cell-mediated hair follicle destruction |
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