USP14 inhibits sensitization-mediated degradation of KDM4D to epigenetically regulate dendritic cell tolerogenic capacity and mitigates airway allergy

Zhang A 1 , Zhang H 2 , Liu L 3 , Zhang H 3 , Mo L 4 , Zhang W 5 Show all authors , Harith HH 6 , Cheng L 7 , Lv J 8 , Tham CL 9 , Yang P 10

Affiliations 

  • 1 Department of Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, China; Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
  • 2 Department of Allergy Medicine, Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China
  • 3 State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China
  • 4 State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China; Department of Respirology and Allergy, Third Affiliated Hospital of Shenzhen University, Shenzhen, China
  • 5 Department of Critical Care Medicine, Second Hospital of Shanxi Medical University, Taiyuan, China
  • 6 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia
  • 7 Department of Emergency Medicine, Second Hospital of Shanxi Medical University, Taiyuan, China
  • 8 Department of Anesthesiology, The first hospital of Shanxi Medical University, Taiyuan, China. Electronic address: jl@sxmu.edu.cn
  • 9 Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia; Natural Medicines and Products Research Laboratory, Institute of Bioscience, Universiti Putra Malaysia, 43400 UPM Serdang, Selangor, Malaysia. Electronic address: chauling@upm.edu.my
  • 10 State Key Laboratory of Respiratory Diseases Allergy Division at Shenzhen University and Institute of Allergy & Immunology, Shenzhen University School of Medicine, Shenzhen, China. Electronic address: pcy2356@163.com
Cell Immunol, 2025 Mar 13;411-412:104943.
PMID: 40088847 DOI: 10.1016/j.cellimm.2025.104943

Abstract

Numerous immune disorders are caused by the dysfunction of dendritic cells (DC). The mechanism has not been fully comprehended yet. This research is designed to regulate the epigenetic status of lysine-specific demethylase 4D (KDM4D) to enhance DC's immune tolerogenic capacity. In this study, an airway allergy (AA) mouse model was established with dust mite extracts (DME) as the specific antigen. A mouse strain carrying Kdm4d-deficient DCs was employed in the experiments to assess the role of KDM4D in modulating DC's immune tolerogenic functions. The results showed that mice carrying Kdm4d-deficient DCs (KO mice) showed spontaneous Th2 polarization in the airways. Reduced quantities of KDM4D were detected in airway naive DCs (nDCs) of AA mice. The parameters of AA response had a negative correlation with the quantity of KDM4D. The immune tolerogenic capacity of airway nDCs was impaired in KO mice as well as in AA mice. The Il10 promoter was found to be hypermethylated in airway nDCs of AA mice and KO mice. The low quantity of deubiquitinating enzyme 14 (USP14) was related to the high level of hyper ubiquitination observed in KDM4D in the Il10 promoter locus of airway nDCs of AA mice. Exposure to recombinant USP14 increased the quantity of KDM4D in nDCs, restoring the immune tolerogenic capacity of nDCs in AA mice. In conclusion, dysfunctional tolerogenicity is caused by low levels of KDM4D in airway nDCs from AA mice. USP14 restores the tolerogenic capacity of nDCs in AA mice and mitigates experimental AA.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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