Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Targeting KAT8 alleviates self-RNA-driven skin inflammation by modulating histone H4 lysine 16 acetylation in psoriasis

Cell Death & Differentiation (2025)Cite this article

Subjects

Abstract

Psoriasis is a persistent inflammatory skin disease characterized by the adverse infiltration of inflammatory cells and epidermal hyperplasia. Self-RNA is the most abundant damage-associated molecular pattern (DAMP) in psoriasis tissues, which triggers and amplifies inflammatory responses through TLR7 pathway. However, the pathogenic effects of self-RNA on immune cell activation and chemotaxis during psoriasis and the underlying mechanisms remain largely unknown. Epigenetic modifications are widely acknowledged to link the environmental signals to gene expression in various immune cells, whose dysfunction tends to cause or worsen various inflammatory diseases. Through a comprehensive analysis of histone modifications in lesional skin from both psoriasis patients and mice, the significantly increased level of histone acetylation at H4 lysine 16 (H4K16ac) in macrophages was found, which was positively correlated with the accumulation of self-RNA in the dermis and psoriasis pathology. Further studies showed that lysine acetyltransferase 8 (KAT8) was responsible for self-RNA-driven H4K16ac modification and psoriasis-associated pathogenic chemokine expression in macrophages of lesional skin. Mechanistically, KAT8 was selectively recruited to the gene promoters of pathogenic chemokines including Cxcl2 and Ccl3 through interaction with AP-1 transcription complex. The auto-acetylation of KAT8 enhanced its acetyltransferase activity. KAT8-mediated H4K16ac modification at these chemokine promoters, coupling with increased chromatin accessibility, facilitated the production and secretion of pro-inflammatory chemokines CXCL2 and CCL3 for neutrophil chemotaxis, neutrophil extracellular traps (NETs) formation and aggravated inflammatory damage in psoriasis. KAT8 deficiency in macrophages or pharmacological inhibition restricted the secretion of macrophage-derived pro-inflammatory chemokines and ameliorated TLR7-dependent tissue inflammatory injury in experimental psoriasis and arthritis model. Taken together, our finding provides new insight into the role of epigenetic modification in self-RNA/TLR7 pathway-dependent immune cell activation and chemotaxis during psoriasis, which proposes the promising therapeutic strategy to control the inflammatory damage and psoriatic skin dysfunction by targeting KAT8 and KAT8-mediated H4K16ac modification in dermis macrophages.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Self-RNA and H4K16ac are upregulated in the epidermis of patients with psoriasis and IMQ-treated mice.
Fig. 2: KAT8 inhibitor ameliorates the psoriasis-like pathology in the IMQ model.
Fig. 3: KAT8 deficiency in macrophages alleviates IMQ-induced psoriasis-like pathological phenotype.
Fig. 4: KAT8 mediates self-RNA-induced pathogenic inflammatory cell infiltration.
Fig. 5: KAT8 is indispensable for ssRNA-triggered chemokine program in macrophages.
Fig. 6: KAT8 selectively binds to gene loci of chemokine genes in AP-1 complex-dependent manner.
Fig. 7: KAT8-mediated H4K16ac modification reprograms the epigenetic landscape for chemokine induction in macrophages.

Similar content being viewed by others

Data availability

Data supporting the present study are available from the corresponding author upon reasonable request. Original images of unprocessed immunoblot are available at Supplementary information.

References

  1. Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker JNWN. Psoriasis. Lancet. 2021;397:1301–15.

    Article  CAS  PubMed  Google Scholar 

  2. Cai Y, Shen X, Ding C, Qi C, Li K, Li X, et al. Pivotal role of dermal IL-17-producing γδ T cells in skin inflammation. Immunity. 2011;35:596–610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature. 2007;445:866–73.

    Article  CAS  PubMed  Google Scholar 

  4. Lou F, Sun Y, Xu Z, Niu L, Wang Z, Deng S, et al. Excessive polyamine generation in keratinocytes promotes self-RNA sensing by dendritic cells in psoriasis. Immunity. 2020;53:204–16.e10.

    Article  CAS  PubMed  Google Scholar 

  5. Brunner PM, Koszik F, Reininger B, Kalb ML, Bauer W, Stingl G. Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages. J Allergy Clin Immunol. 2013;132:1184–93.e8.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang L-J, Sen GL, Ward NL, Johnston A, Chun K, Chen Y, et al. Antimicrobial peptide LL37 and MAVS signaling drive interferon-β production by epidermal keratinocytes during skin injury. Immunity. 2016;45:119–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ganguly D, Chamilos G, Lande R, Gregorio J, Meller S, Facchinetti V, et al. Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8. J Exp Med. 2009;206:12.

    Article  Google Scholar 

  8. Tokuyama M, Mabuchi T. New treatment addressing the pathogenesis of psoriasis. International J Mol Sci. 2020;21:7488.

    Article  CAS  Google Scholar 

  9. Romhányi D, Szabó K, Kemény L, Groma G. Histone and histone acetylation-related alterations of gene expression in uninvolved psoriatic skin and their effects on cell proliferation, differentiation, and immune responses. Int J Mol Sci. 2023;24:14551.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yao Q, Epstein CB, Banskota S, Issner R, Kim Y, Bernstein BE, et al. Epigenetic alterations in keratinocyte carcinoma. J Invest Dermatol. 2021;141:1207–18.

    Article  CAS  PubMed  Google Scholar 

  11. Masalha M. H3K27Ac modification and gene expression in psoriasis. J Dermatol Sci. 2021;103:93–100.

    Article  CAS  PubMed  Google Scholar 

  12. Nascimento-Filho CHV, Silveira EJD, Goloni-Bertollo EM, De Souza LB, Squarize CH, Castilho RM. Skin wound healing triggers epigenetic modifications of histone H4. J Transl Med. 2020;18:138.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, et al. Psoriasis. Nat Rev Dis Prim. 2016;2:16082.

    Article  PubMed  Google Scholar 

  14. Valerio DG, Xu H, Eisold ME, Woolthuis CM, Pandita TK, Armstrong SA. Histone acetyltransferase activity of MOF is required for adult but not early fetal hematopoiesis in mice. Blood. 2017;129:48–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Mellert H, Sykes SM, Murphy ME, McMahon SB. The ARF/oncogene pathway activates p53 acetylation within the DNA binding domain. Cell Cycle (Georget, Tex). 2007;6:1304–6.

    Article  CAS  Google Scholar 

  16. Füllgrabe J, Klionsky DJ, Joseph B. Histone post-translational modifications regulate autophagy flux and outcome. Autophagy. 2013;9:1621–3.

    Article  PubMed  Google Scholar 

  17. Wu Y. Disrupting the phase separation of KAT8–IRF1 diminishes PD-L1 expression and promotes antitumor immunity. Nature Cancer. 2023;4:382–400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Huai W, Liu X, Wang C, Zhang Y, Chen X, Chen X, et al. KAT8 selectively inhibits antiviral immunity by acetylating IRF3. J Exp Med. 2019;216:772–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Herster F. Neutrophil extracellular trap-associated RNA and LL37 enable self-amplifying inflammation in psoriasis. Nat Commun. 2020;11:105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Balsini P, Weinzettl P, Samardzic D, Zila N, Buchberger M, Freystätter C et al. Stiffness-dependent lysyl oxidase regulation through hypoxia-inducing factor 1 drives extracellular matrix modifications in psoriasis. J Invest Dermatol. 2024; 26:1653–69.

  21. Suárez-Fariñas M, Li K, Fuentes-Duculan J, Hayden K, Brodmerkel C, Krueger JG. Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis. J Invest Dermatol. 2012;132:2552–64.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Peng L, Liu W, Cheng Y, Chen L, Shen Z. IL-17A/F double producing T cells, unstable tregs and quiescent TRMs in clinically healed lesions are potential cellular candidates for recurrence of psoriasis. Clin Immunol. 2024;266:110328.

    Article  CAS  PubMed  Google Scholar 

  23. Gessl I, Hana CA, Deimel T, Durechova M, Hucke M, Konzett V, et al. Tenderness and radiographic progression in rheumatoid arthritis and psoriatic arthritis. Ann Rheum Dis. 2023;82:344–50.

    Article  PubMed  Google Scholar 

  24. El Bably MM, Abdel Aziz DM, Adly NN, Ali MA, Khedr AS, El Leithy SA. Galectin-1 in Psoriatic arthritis, Psoriasis, Rheumatoid arthritis and its relation with disease activity and skin lesion. Egypt J Immunol. 2023;30:73–82.

    Article  PubMed  Google Scholar 

  25. Chamberlain ND, Kim S, Vila OM, Volin MV, Volkov S, Pope RM, et al. Ligation of TLR7 by rheumatoid arthritis synovial fluid single strand RNA induces transcription of TNFα in monocytes.Ann Rheum Dis. 2013;72:418–26.

  26. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–29.

    Article  CAS  PubMed  Google Scholar 

  27. Füllgrabe J, Lynch-Day MA, Heldring N, Li W, Struijk RB, Ma Q, et al. The histone H4 lysine 16 acetyltransferase hMOF regulates the outcome of autophagy. Nature. 2013;500:468–71.

  28. Zhu Y, Wu Z, Yan W, Shao F, Ke B, Jiang X, et al. Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis. EMBO Mol Med. 2022;14:e14455.

    Article  CAS  PubMed  Google Scholar 

  29. Yang Y, Csakai A, Jiang S, Smith C, Tanji H, Huang J, et al. Tetrasubstituted imidazoles as incognito Toll-like receptor 8 a(nta)gonists. Nat Commun. 2021;12:4351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Klopp-Schulze L, Shaw JV, Dong JQ, Khandelwal A, Vazquez-Mateo C, Goteti K. Applying modeling and simulations for rational dose selection of novel toll-like receptor 7/8 inhibitor enpatoran for indications of high medical need. Clin Pharm Ther. 2022;112:297–306.

    Article  CAS  Google Scholar 

  31. McKinnon JE, Santiaguel J, Murta de Oliveira C, Yu D, Khursheed M, Moreau F, et al. Enpatoran in COVID-19 pneumonia: safety and efficacy results from a phase II randomized trial. Clin Transl Sci. 2023;16:2640–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Port A, Shaw JV, Klopp-Schulze L, Bytyqi A, Vetter C, Hussey E, et al. Phase 1 study in healthy participants of the safety, pharmacokinetics, and pharmacodynamics of enpatoran (M5049), a dual antagonist of toll-like receptors 7 and 8. Pharmacol Res Perspect. 2021;9:e00842.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang P, Su Y, Zhao M, Huang W, Lu Q. Abnormal histone modifications in PBMCs from patients with psoriasis vulgaris. Eur J Dermatol. 2011;21:552–7.

    Article  CAS  PubMed  Google Scholar 

  34. Samata M, Alexiadis A, Richard G, Georgiev P, Nuebler J, Kulkarni T, et al. Intergenerationally maintained histone h4 lysine 16 acetylation is instructive for future gene activation. Cell. 2020;182:127–44.

    Article  CAS  PubMed  Google Scholar 

  35. Pessoa Rodrigues C, Chatterjee A, Wiese M, Stehle T, Szymanski W, Shvedunova M, et al. Histone H4 lysine 16 acetylation controls central carbon metabolism and diet-induced obesity in mice. Nat Commun. 2021;12:6212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang X, Liu H, Zhou JQ, Krick S, Barnes JW, Thannickal VJ, et al. Modulation of H4K16Ac levels reduces pro-fibrotic gene expression and mitigates lung fibrosis in aged mice. Theranostics. 2022;12:530–41.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Chen F, Chen H, Jia Y, Lu H, Tan Q, Zhou X. miR-149-5p inhibition reduces alzheimer’s disease β-amyloid generation in 293/APPsw cells by upregulating H4K16ac via KAT8. Exp Ther Med. 2020;20:88.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zippo A, Serafini R, Rocchigiani M, Pennacchini S, Krepelova A, Oliviero S. Histone crosstalk between H3S10ph and H4K16ac generates a histone code that mediates transcription elongation. Cell. 2009;138:1122–36.

    Article  CAS  PubMed  Google Scholar 

  39. Cai W-T, Guan P, Lin M-X, Fu B, Wu B. Sirt1 suppresses MCP-1 production during the intervertebral disc degeneration by inactivating AP-1 subunits c-fos/c-jun. Eur Rev Med Pharm Sci. 2020;24:5895–904.

    Google Scholar 

  40. Novoszel P, Holcmann M, Stulnig G, De Sa Fernandes C, Zyulina V, Borek I, et al. Psoriatic skin inflammation is promoted by c-Jun/AP-1-dependent CCL2 and IL-23 expression in dendritic cells. EMBO Mol Med. 2021;13:e12409.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Bhagchandani S, Johnson JA, Irvine DJ. Evolution of Toll-like receptor 7/8 agonist therapeutics and their delivery approaches: from antiviral formulations to vaccine adjuvants. Advanced Drug Deliv Rev. 2021;175:113803.

    Article  CAS  Google Scholar 

  42. Kaisho T, Tanaka T. Turning NF-kappaB and IRFs on and off in DC. Trends Immunol. 2008;29:329–36.

    Article  CAS  PubMed  Google Scholar 

  43. Larsen SB, Cowley CJ, Sajjath SM, Barrows D, Yang Y, Carroll TS, et al. Establishment, maintenance, and recall of inflammatory memory. Cell Stem Cell. 2021;28:1758–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sheikh BN, Guhathakurta S, Akhtar A. The non-specific lethal (NSL) complex at the crossroads of transcriptional control and cellular homeostasis. EMBO Rep. 2019;20:e47630.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci. 2019;20:1475.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Van Der Fits L, Mourits S, Voerman JSA, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol. 2009;182:5836–45.

    Article  PubMed  Google Scholar 

  47. Zhang S, Zhang Y, Duan X, Wang B, Zhan Z. Targeting NPM1 epigenetically promotes postinfarction cardiac repair by reprogramming reparative macrophage metabolism. Circulation. 2024;149:1982–2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang Y, Gao Y, Jiang Y, Ding Y, Chen H, Xiang Y, et al. Histone demethylase KDM5B licenses macrophage-mediated inflammatory responses by repressing Nfkbia transcription. Cell Death Differ. 2023;30:1279–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zhou Q, Zhang Y, Wang B, Zhou W, Bi Y, Huai W, et al. KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling. Cell Mol Immunol. 2020;17:834–42.

    Article  CAS  PubMed  Google Scholar 

  50. Yong L, Yu Y, Li B, Ge H, Zhen Q, Mao Y, et al. Calcium/calmodulin-dependent protein kinase IV promotes imiquimod-induced psoriatic inflammation via macrophages and keratinocytes in mice. Nat Commun. 2022;13:4255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Key Research & Development Program of China (2023YFC2307302, 2023YFC2307000), the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2024ZD0529003), the National Natural Science Foundation of China (82271797, 82341065, 82371825 and 32400727), the program of Shanghai outstanding academic leader in public health subject (GWVI-11.2-XD29), the experimental animal program sponsored by the Science and Technology Commission of Shanghai Municipality (23141902300), the Natural Science Foundation of Shanghai (24ZR1481100), the Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (24CGA43), the Postadoctoral Fellowship Program for Innovative Talents and China Postdoctoral Science Foundation, and the Open Research Fund of Basic Medicine College of Naval Medical University (JCKFKT-ZD-002).

Author information

Author notes

  1. These authors contributed equally: Yan Xiang, Yuyu Jiang, Zeting Wang, Xiaohui Wang.

Authors and Affiliations

  1. National Key Laboratory of Immunity & Inflammation, Naval Medical University, Shanghai, China

    Yan Xiang, Yuyu Jiang, Zeting Wang & Xingguang Liu

  2. Department of Pathogen Biology, Naval Medical University, Shanghai, China

    Yan Xiang, Yuyu Jiang, Zeting Wang, Yingying Ding, Bing Rui, Chunyan Zhao, Xiangyu Li & Xingguang Liu

  3. School of Health Science and Engineering, University of Shanghai for Science and Technology, Shanghai, China

    Xiaohui Wang

  4. Shanghai Institute of Transplantation, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Lijie Ma & Zhenzhen Zhan

  5. Shanghai Skin Disease Hospital, Skin Disease Hospital of Tongji University, Shanghai, China

    Mingyuan Xu

  6. Naval Medical Center, Naval Medical University, Shanghai, China

    Yunkai Zhang

  7. Key Laboratory of Biological Defense, Ministry of Education, Shanghai, China

    Xingguang Liu

Authors
  1. Yan Xiang
    View author publications

    Search author on:PubMed Google Scholar

  2. Yuyu Jiang
    View author publications

    Search author on:PubMed Google Scholar

  3. Zeting Wang
    View author publications

    Search author on:PubMed Google Scholar

  4. Xiaohui Wang
    View author publications

    Search author on:PubMed Google Scholar

  5. Lijie Ma
    View author publications

    Search author on:PubMed Google Scholar

  6. Yingying Ding
    View author publications

    Search author on:PubMed Google Scholar

  7. Bing Rui
    View author publications

    Search author on:PubMed Google Scholar

  8. Chunyan Zhao
    View author publications

    Search author on:PubMed Google Scholar

  9. Xiangyu Li
    View author publications

    Search author on:PubMed Google Scholar

  10. Mingyuan Xu
    View author publications

    Search author on:PubMed Google Scholar

  11. Yunkai Zhang
    View author publications

    Search author on:PubMed Google Scholar

  12. Zhenzhen Zhan
    View author publications

    Search author on:PubMed Google Scholar

  13. Xingguang Liu
    View author publications

    Search author on:PubMed Google Scholar

Contributions

YX, YJ, ZW, and XW performed experiments, analyzed data, and interpreted results. YX designed experiments and drafted the manuscript. LM, YD, BR, CZ, and XL performed experiments and collected data. MX provided the resources; XL, ZZ, and YZ conceived the study, designed experiments, analyzed data, revised the manuscript, and provided funding for this study.

Corresponding authors

Correspondence to Yunkai Zhang, Zhenzhen Zhan or Xingguang Liu.

Ethics declarations

Competing interests

The authors declare no competing interests.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

All animal experiments were conducted in strict accordance with the Guidelines for the Care and Use of Laboratory Animals of Naval Medical University, China, and approved by the Animal Ethics Committee of Naval Medical University. Informed consents were obtained from all participants. Experiments using human samples were approved by the Ethics Committee of Skin Disease Hospital of Tongji University, and conducted in accordance with the Declaration of Helsinki.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiang, Y., Jiang, Y., Wang, Z. et al. Targeting KAT8 alleviates self-RNA-driven skin inflammation by modulating histone H4 lysine 16 acetylation in psoriasis. Cell Death Differ (2025). https://doi.org/10.1038/s41418-025-01547-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41418-025-01547-y

Search

Advanced search

Quick links