Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis
Summary: One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-11-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014614 |
| _version_ | 1827630407046135808 |
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| author | Jiaqing Hao Jianyu Yu Matthew S. Yorek Chi-Li Yu R. Marshall Pope Michael S. Chimenti Yiqin Xiong Aloysius Klingelhutz Ali Jabbari Bing Li |
| author_facet | Jiaqing Hao Jianyu Yu Matthew S. Yorek Chi-Li Yu R. Marshall Pope Michael S. Chimenti Yiqin Xiong Aloysius Klingelhutz Ali Jabbari Bing Li |
| author_sort | Jiaqing Hao |
| collection | DOAJ |
| description | Summary: One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis. |
| first_indexed | 2024-03-09T14:05:20Z |
| format | Article |
| id | doaj.art-ebb801bccbcd43f59f3b0a20cf768831 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-09T14:05:20Z |
| publishDate | 2023-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-ebb801bccbcd43f59f3b0a20cf7688312023-11-30T05:07:17ZengElsevierCell Reports2211-12472023-11-014211113449Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasisJiaqing Hao0Jianyu Yu1Matthew S. Yorek2Chi-Li Yu3R. Marshall Pope4Michael S. Chimenti5Yiqin Xiong6Aloysius Klingelhutz7Ali Jabbari8Bing Li9Department of Pathology, University of Iowa, Iowa City, IA, USADepartment of Pathology, University of Iowa, Iowa City, IA, USADepartment of Pathology, University of Iowa, Iowa City, IA, USAProteomics Facility, University of Iowa, Iowa City, IA, USAProteomics Facility, University of Iowa, Iowa City, IA, USAIowa Institute of Human Genetics, University of Iowa, Iowa City, IA, USADepartment of Pathology, University of Iowa, Iowa City, IA, USADepartment of Microbiology and Immunology, University of Iowa, Iowa City, IA, USADepartment of Dermatology, University of Iowa, Iowa City, IA, USA; Iowa City VA Medical Center, Iowa City, IA, USADepartment of Pathology, University of Iowa, Iowa City, IA, USA; Corresponding authorSummary: One of the hallmarks of intractable psoriasis is neutrophil infiltration in skin lesions. However, detailed molecular mechanisms of neutrophil chemotaxis and activation remain unclear. Here, we demonstrate a significant upregulation of epidermal fatty acid binding protein (E-FABP, FABP5) in the skin of human psoriasis and psoriatic mouse models. Genetic deletion of FABP5 in mice by global knockout and keratinocyte conditional (Krt6a-Cre) knockout, but not myeloid cell conditional (LysM-Cre) knockout, attenuates psoriatic symptoms. Immunophenotypic analysis shows that FABP5 deficiency specifically reduces skin recruitment of Ly6G+ neutrophils. Mechanistically, activated keratinocytes produce chemokines and cytokines that trigger neutrophil chemotaxis and activation in an FABP5-dependent manner. Proteomic analysis further identifies that FABP5 interacts with valosin-containing protein (VCP), a key player in NF-κB signaling activation. Silencing of FABP5, VCP, or both inhibits NF-κB/neutrophil chemotaxis signaling. Collectively, these data demonstrate dysregulated FABP5 as a molecular mechanism promoting NF-κB signaling and neutrophil infiltration in psoriasis pathogenesis.http://www.sciencedirect.com/science/article/pii/S2211124723014614CP: Immunology |
| spellingShingle | Jiaqing Hao Jianyu Yu Matthew S. Yorek Chi-Li Yu R. Marshall Pope Michael S. Chimenti Yiqin Xiong Aloysius Klingelhutz Ali Jabbari Bing Li Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis Cell Reports CP: Immunology |
| title | Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis |
| title_full | Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis |
| title_fullStr | Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis |
| title_full_unstemmed | Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis |
| title_short | Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis |
| title_sort | keratinocyte fabp5 vcp complex mediates recruitment of neutrophils in psoriasis |
| topic | CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014614 |
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