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Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice

Author

Listed:
  • Lucas F. Loffredo

    (Columbia University)

  • Anmol Kustagi

    (Columbia University)

  • Olivia R. Ringham

    (Columbia University)

  • Fangda Li

    (Columbia University)

  • Kenia de los Santos-Alexis

    (Columbia University)

  • Anjali Saqi

    (Columbia University Irving Medical Center)

  • Nicholas Arpaia

    (Columbia University
    Columbia University)

Abstract

Amphiregulin (Areg), a growth factor produced by regulatory T (Treg) cells to facilitate tissue repair, contains a heparan sulfate (HS) binding domain. How HS, a highly sulfated glycan subtype that alters growth factor signaling, influences Areg repair functions is unclear. Here we report that inhibition of HS in various cell lines and primary lung mesenchymal cells (LMC) qualitatively alters Areg downstream signaling. Utilization of a panel of cell lines with targeted deletions in HS synthesis–related genes identifies the glypican family of HS proteoglycans as critical for Areg signaling. In the context of influenza A virus (IAV) infection in vivo, an Areg-responsive subset of reparative LMC upregulate glypican-4 and HS; conditional deletion of HS primarily within this LMC subset results in reduced repair characteristics following IAV infection. This study demonstrates that HS on a specific lung mesenchymal population is a mediator of Treg cell–derived Areg reparative signaling.

Suggested Citation

  • Lucas F. Loffredo & Anmol Kustagi & Olivia R. Ringham & Fangda Li & Kenia de los Santos-Alexis & Anjali Saqi & Nicholas Arpaia, 2025. "Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57362-z
    DOI: 10.1038/s41467-025-57362-z
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    References listed on IDEAS

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    1. Minako Ito & Kyoko Komai & Setsuko Mise-Omata & Mana Iizuka-Koga & Yoshiko Noguchi & Taisuke Kondo & Ryota Sakai & Kazuhiko Matsuo & Takashi Nakayama & Osamu Yoshie & Hiroko Nakatsukasa & Shunsuke Chi, 2019. "Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery," Nature, Nature, vol. 565(7738), pages 246-250, January.
    2. Kyle J. Travaglini & Ahmad N. Nabhan & Lolita Penland & Rahul Sinha & Astrid Gillich & Rene V. Sit & Stephen Chang & Stephanie D. Conley & Yasuo Mori & Jun Seita & Gerald J. Berry & Joseph B. Shrager , 2020. "A molecular cell atlas of the human lung from single-cell RNA sequencing," Nature, Nature, vol. 587(7835), pages 619-625, November.
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