IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-31132-7.html
   My bibliography  Save this article

CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes

Author

Listed:
  • Chao Yang

    (Hospital for Special Surgery)

  • Mahesh Bachu

    (Hospital for Special Surgery)

  • Yong Du

    (Hospital for Special Surgery)

  • Caroline Brauner

    (Hospital for Special Surgery)

  • Ruoxi Yuan

    (Hospital for Special Surgery)

  • Marie Dominique Ah Kioon

    (Hospital for Special Surgery)

  • Giancarlo Chesi

    (Hospital for Special Surgery)

  • Franck J. Barrat

    (Hospital for Special Surgery
    Weill Cornell Medicine
    Weill Cornell Medicine)

  • Lionel B. Ivashkiv

    (Hospital for Special Surgery
    Weill Cornell Medicine
    Weill Cornell Medicine)

Abstract

Regulation of endosomal Toll-like receptor (TLR) responses by the chemokine CXCL4 is implicated in inflammatory and fibrotic diseases, with CXCL4 proposed to potentiate TLR responses by binding to nucleic acid TLR ligands and facilitating their endosomal delivery. Here we report that in human monocytes/macrophages, CXCL4 initiates signaling cascades and downstream epigenomic reprogramming that change the profile of the TLR8 response by selectively amplifying inflammatory gene transcription and interleukin (IL)−1β production, while partially attenuating the interferon response. Mechanistically, costimulation by CXCL4 and TLR8 synergistically activates TBK1 and IKKε, repurposes these kinases towards an inflammatory response via coupling with IRF5, and activates the NLRP3 inflammasome. CXCL4 signaling, in a cooperative and synergistic manner with TLR8, induces chromatin remodeling and activates de novo enhancers associated with inflammatory genes. Our findings thus identify new regulatory mechanisms of TLR responses relevant for cytokine storm, and suggest targeting the TBK1-IKKε-IRF5 axis may be beneficial in inflammatory diseases.

Suggested Citation

  • Chao Yang & Mahesh Bachu & Yong Du & Caroline Brauner & Ruoxi Yuan & Marie Dominique Ah Kioon & Giancarlo Chesi & Franck J. Barrat & Lionel B. Ivashkiv, 2022. "CXCL4 synergizes with TLR8 for TBK1-IRF5 activation, epigenomic remodeling and inflammatory response in human monocytes," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31132-7
    DOI: 10.1038/s41467-022-31132-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-31132-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-31132-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Grigory Ryzhakov & Hannah Almuttaqi & Alastair L. Corbin & Dorothée L. Berthold & Tariq Khoyratty & Hayley L. Eames & Samuel Bullers & Claire Pearson & Zhichao Ai & Kristina Zec & Sarah Bonham & Roman, 2021. "Defactinib inhibits PYK2 phosphorylation of IRF5 and reduces intestinal inflammation," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    2. Elizabeth A. Leadbetter & Ian R. Rifkin & Andreas M. Hohlbaum & Britte C. Beaudette & Mark J. Shlomchik & Ann Marshak-Rothstein, 2002. "Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors," Nature, Nature, vol. 416(6881), pages 603-607, April.
    3. Roberto Lande & Josh Gregorio & Valeria Facchinetti & Bithi Chatterjee & Yi-Hong Wang & Bernhard Homey & Wei Cao & Yui-Hsi Wang & Bing Su & Frank O. Nestle & Tomasz Zal & Ira Mellman & Jens-Michael Sc, 2007. "Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide," Nature, Nature, vol. 449(7162), pages 564-569, October.
    4. Mette Bentsen & Philipp Goymann & Hendrik Schultheis & Kathrin Klee & Anastasiia Petrova & René Wiegandt & Annika Fust & Jens Preussner & Carsten Kuenne & Thomas Braun & Johnny Kim & Mario Looso, 2020. "ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation," Nature Communications, Nature, vol. 11(1), pages 1-11, December.
    5. Christopher A. Odhams & Amy L. Roberts & Susan K. Vester & Carolina S. T. Duarte & Charlie T. Beales & Alexander J. Clarke & Sonja Lindinger & Samuel J. Daffern & Antonino Zito & Lingyan Chen & Leonar, 2019. "Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    6. Roberto Lande & Ernest Y. Lee & Raffaella Palazzo & Barbara Marinari & Immacolata Pietraforte & Giancarlo Santiago Santos & Yves Mattenberger & Francesca Spadaro & Katia Stefanantoni & Nicoletta Ianna, 2019. "CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    7. Leonhard X. Heinz & JangEun Lee & Utkarsh Kapoor & Felix Kartnig & Vitaly Sedlyarov & Konstantinos Papakostas & Adrian César-Razquin & Patrick Essletzbichler & Ulrich Goldmann & Adrijana Stefanovic & , 2020. "TASL is the SLC15A4-associated adaptor for IRF5 activation by TLR7–9," Nature, Nature, vol. 581(7808), pages 316-322, May.
    8. Katrin D. Mayer-Barber & Bruno B. Andrade & Sandra D. Oland & Eduardo P. Amaral & Daniel L. Barber & Jacqueline Gonzales & Steven C. Derrick & Ruiru Shi & Nathella Pavan Kumar & Wang Wei & Xing Yuan &, 2014. "Host-directed therapy of tuberculosis based on interleukin-1 and type I interferon crosstalk," Nature, Nature, vol. 511(7507), pages 99-103, July.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Andras Boeszoermenyi & Léa Bernaleau & Xudong Chen & Felix Kartnig & Min Xie & Haobo Zhang & Sensen Zhang & Maeva Delacrétaz & Anna Koren & Ann-Katrin Hopp & Vojtech Dvorak & Stefan Kubicek & Daniel A, 2023. "A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    2. Xudong Chen & Min Xie & Sensen Zhang & Marta Monguió-Tortajada & Jian Yin & Chang Liu & Youqi Zhang & Maeva Delacrétaz & Mingyue Song & Yixue Wang & Lin Dong & Qiang Ding & Boda Zhou & Xiaolin Tian & , 2023. "Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    3. Feiyang Ma & Olesya Plazyo & Allison C. Billi & Lam C. Tsoi & Xianying Xing & Rachael Wasikowski & Mehrnaz Gharaee-Kermani & Grace Hile & Yanyun Jiang & Paul W. Harms & Enze Xing & Joseph Kirma & Jing, 2023. "Single cell and spatial sequencing define processes by which keratinocytes and fibroblasts amplify inflammatory responses in psoriasis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    4. Tomalika R. Ullah & Matt D. Johansen & Katherine R. Balka & Rebecca L. Ambrose & Linden J. Gearing & James Roest & Julian P. Vivian & Sunil Sapkota & W. Samantha N. Jayasekara & Daniel S. Wenholz & Vi, 2023. "Pharmacological inhibition of TBK1/IKKε blunts immunopathology in a murine model of SARS-CoV-2 infection," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    5. Tao Zhu & Chunjiao Xia & Ranran Yu & Xinkai Zhou & Xingbing Xu & Lin Wang & Zhanxiang Zong & Junjiao Yang & Yinmeng Liu & Luchang Ming & Yuxin You & Dijun Chen & Weibo Xie, 2024. "Comprehensive mapping and modelling of the rice regulome landscape unveils the regulatory architecture underlying complex traits," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    6. Hai Ni & Yinuo Wang & Kai Yao & Ling Wang & Jiancheng Huang & Yongfang Xiao & Hongyao Chen & Bo Liu & Cliff Y. Yang & Jijun Zhao, 2024. "Cyclical palmitoylation regulates TLR9 signalling and systemic autoimmunity in mice," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Remzi Onur Eren & Göksu Gökberk Kaya & Robin Schwarzer & Manolis Pasparakis, 2024. "IKKε and TBK1 prevent RIPK1 dependent and independent inflammation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    8. Zhenhui Zhong & Yafei Wang & Ming Wang & Fan Yang & Quentin Angelo Thomas & Yan Xue & Yaxin Zhang & Wanlu Liu & Yasaman Jami-Alahmadi & Linhao Xu & Suhua Feng & Sebastian Marquardt & James A. Wohlschl, 2022. "Histone chaperone ASF1 mediates H3.3-H4 deposition in Arabidopsis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    9. Dhurjhoti Saha & Solomon Hailu & Arjan Hada & Junwoo Lee & Jie Luo & Jeff A. Ranish & Yuan-chi Lin & Kyle Feola & Jim Persinger & Abhinav Jain & Bin Liu & Yue Lu & Payel Sen & Blaine Bartholomew, 2023. "The AT-hook is an evolutionarily conserved auto-regulatory domain of SWI/SNF required for cell lineage priming," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Joyce J. Thompson & Daniel J. Lee & Apratim Mitra & Sarah Frail & Ryan K. Dale & Pedro P. Rocha, 2022. "Extensive co-binding and rapid redistribution of NANOG and GATA6 during emergence of divergent lineages," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    11. Antonio Julià & Alba Erra & Carles Palacio & Carlos Tomas & Xavier Sans & Pere Barceló & Sara Marsal, 2009. "An Eight-Gene Blood Expression Profile Predicts the Response to Infliximab in Rheumatoid Arthritis," PLOS ONE, Public Library of Science, vol. 4(10), pages 1-8, October.
    12. Moritz Binder & Raphael E. Szalat & Srikanth Talluri & Mariateresa Fulciniti & Hervé Avet-Loiseau & Giovanni Parmigiani & Mehmet K. Samur & Nikhil C. Munshi, 2024. "Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    13. Timothy D. Arthur & Jennifer P. Nguyen & Agnieszka D’Antonio-Chronowska & Hiroko Matsui & Nayara S. Silva & Isaac N. Joshua & André D. Luchessi & William W. Young Greenwald & Matteo D’Antonio & Martin, 2024. "Complex regulatory networks influence pluripotent cell state transitions in human iPSCs," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    14. Urszula Radzikowska & Andrzej Eljaszewicz & Ge Tan & Nino Stocker & Anja Heider & Patrick Westermann & Silvio Steiner & Anita Dreher & Paulina Wawrzyniak & Beate Rückert & Juan Rodriguez-Coira & Damir, 2023. "Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    15. Aditya Kshirsagar & Svetlana Maslov Doroshev & Anna Gorelik & Tsviya Olender & Tamar Sapir & Daisuke Tsuboi & Irit Rosenhek-Goldian & Sergey Malitsky & Maxim Itkin & Amir Argoetti & Yael Mandel-Gutfre, 2023. "LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    16. Tae Gun Kang & Kee Woong Kwon & Kyungsoo Kim & Insuk Lee & Myeong Joon Kim & Sang-Jun Ha & Sung Jae Shin, 2022. "Viral coinfection promotes tuberculosis immunopathogenesis by type I IFN signaling-dependent impediment of Th1 cell pulmonary influx," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    17. Shengen Shawn Hu & Lin Liu & Qi Li & Wenjing Ma & Michael J. Guertin & Clifford A. Meyer & Ke Deng & Tingting Zhang & Chongzhi Zang, 2022. "Intrinsic bias estimation for improved analysis of bulk and single-cell chromatin accessibility profiles using SELMA," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    18. Tânia F. Custódio & Maxime Killer & Dingquan Yu & Virginia Puente & Daniel P. Teufel & Alexander Pautsch & Gisela Schnapp & Marc Grundl & Jan Kosinski & Christian Löw, 2023. "Molecular basis of TASL recruitment by the peptide/histidine transporter 1, PHT1," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    19. Yuyan Cheng & Yuqin Yin & Alice Zhang & Alexander M. Bernstein & Riki Kawaguchi & Kun Gao & Kyra Potter & Hui-Ya Gilbert & Yan Ao & Jing Ou & Catherine J. Fricano-Kugler & Jeffrey L. Goldberg & Zhigan, 2022. "Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    20. Pin Lyu & Maria Iribarne & Dmitri Serjanov & Yijie Zhai & Thanh Hoang & Leah J. Campbell & Patrick Boyd & Isabella Palazzo & Mikiko Nagashima & Nicholas J. Silva & Peter F. Hitchcock & Jiang Qian & Da, 2023. "Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina," Nature Communications, Nature, vol. 14(1), pages 1-21, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31132-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.