Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice
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 t...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-03-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-57362-z |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849762520446795776 |
|---|---|
| author | Lucas F. Loffredo Anmol Kustagi Olivia R. Ringham Fangda Li Kenia de los Santos-Alexis Anjali Saqi Nicholas Arpaia |
| author_facet | Lucas F. Loffredo Anmol Kustagi Olivia R. Ringham Fangda Li Kenia de los Santos-Alexis Anjali Saqi Nicholas Arpaia |
| author_sort | Lucas F. Loffredo |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e5a09f9b04e34345afa2208728eb9abc |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-e5a09f9b04e34345afa2208728eb9abc2025-08-20T03:05:43ZengNature PortfolioNature Communications2041-17232025-03-0116111610.1038/s41467-025-57362-zHeparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in miceLucas F. Loffredo0Anmol Kustagi1Olivia R. Ringham2Fangda Li3Kenia de los Santos-Alexis4Anjali Saqi5Nicholas Arpaia6Department of Microbiology & Immunology, Columbia UniversityDepartment of Microbiology & Immunology, Columbia UniversityDepartment of Microbiology & Immunology, Columbia UniversityDepartment of Microbiology & Immunology, Columbia UniversityDepartment of Microbiology & Immunology, Columbia UniversityDepartment of Pathology and Cell Biology, Columbia University Irving Medical CenterDepartment of Microbiology & Immunology, Columbia UniversityAbstract 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.https://doi.org/10.1038/s41467-025-57362-z |
| spellingShingle | Lucas F. Loffredo Anmol Kustagi Olivia R. Ringham Fangda Li Kenia de los Santos-Alexis Anjali Saqi Nicholas Arpaia Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice Nature Communications |
| title | Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice |
| title_full | Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice |
| title_fullStr | Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice |
| title_full_unstemmed | Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice |
| title_short | Heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza A virus infection in mice |
| title_sort | heparan sulfate regulates amphiregulin programming of tissue reparative lung mesenchymal cells during influenza a virus infection in mice |
| url | https://doi.org/10.1038/s41467-025-57362-z |
| work_keys_str_mv | AT lucasfloffredo heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT anmolkustagi heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT oliviarringham heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT fangdali heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT keniadelossantosalexis heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT anjalisaqi heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice AT nicholasarpaia heparansulfateregulatesamphiregulinprogrammingoftissuereparativelungmesenchymalcellsduringinfluenzaavirusinfectioninmice |