ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis
Inducible T cell co-stimulator (ICOS), an immune checkpoint protein expressed on activated T cells and its unique ligand, ICOSL, which is expressed on antigen-presenting cells and non-hematopoietic cells, have been extensively investigated in the immune response. Recent findings showed that a solubl...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.992614/full |
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| author | Gustavo Ferreira Alves Ian Stoppa Eleonora Aimaretti Chiara Monge Raffaella Mastrocola Elisa Porchietto Giacomo Einaudi Debora Collotta Ilaria Bertocchi Elena Boggio Casimiro Luca Gigliotti Nausicaa Clemente Manuela Aragno Daniel Fernandes Carlo Cifani Christoph Thiemermann Chiara Dianzani Umberto Dianzani Massimo Collino |
| author_facet | Gustavo Ferreira Alves Ian Stoppa Eleonora Aimaretti Chiara Monge Raffaella Mastrocola Elisa Porchietto Giacomo Einaudi Debora Collotta Ilaria Bertocchi Elena Boggio Casimiro Luca Gigliotti Nausicaa Clemente Manuela Aragno Daniel Fernandes Carlo Cifani Christoph Thiemermann Chiara Dianzani Umberto Dianzani Massimo Collino |
| author_sort | Gustavo Ferreira Alves |
| collection | DOAJ |
| description | Inducible T cell co-stimulator (ICOS), an immune checkpoint protein expressed on activated T cells and its unique ligand, ICOSL, which is expressed on antigen-presenting cells and non-hematopoietic cells, have been extensively investigated in the immune response. Recent findings showed that a soluble recombinant form of ICOS (ICOS-Fc) can act as an innovative immunomodulatory drug as both antagonist of ICOS and agonist of ICOSL, modulating cytokine release and cell migration to inflamed tissues. Although the ICOS-ICOSL pathway has been poorly investigated in the septic context, a few studies have reported that septic patients have reduced ICOS expression in whole blood and increased serum levels of osteopontin (OPN), that is another ligand of ICOSL. Thus, we investigated the pathological role of the ICOS-ICOSL axis in the context of sepsis and the potential protective effects of its immunomodulation by administering ICOS-Fc in a murine model of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in five-month-old male wild-type (WT) C57BL/6, ICOS-/-, ICOSL-/- and OPN-/- mice. One hour after the surgical procedure, either CLP or Sham (control) mice were randomly assigned to receive once ICOS-Fc, F119SICOS-Fc, a mutated form uncapable to bind ICOSL, or vehicle intravenously. Organs and plasma were collected 24 h after surgery for analyses. When compared to Sham mice, WT mice that underwent CLP developed within 24 h a higher clinical severity score, a reduced body temperature, an increase in plasma cytokines (TNF-α, IL-1β, IL-6, IFN-γ and IL-10), liver injury (AST and ALT) and kidney (creatinine and urea) dysfunction. Administration of ICOS-Fc to WT CLP mice reduced all of these abnormalities caused by sepsis. Similar beneficial effects were not seen in CLP-mice treated with F119SICOS-Fc. Treatment of CLP-mice with ICOS-Fc also attenuated the sepsis-induced local activation of FAK, P38 MAPK and NLRP3 inflammasome. ICOS-Fc seemed to act at both sides of the ICOS-ICOSL interaction, as the protective effect was lost in septic knockout mice for the ICOS or ICOSL genes, whereas it was maintained in OPN knockout mice. Collectively, our data show the beneficial effects of pharmacological modulation of the ICOS-ICOSL pathway in counteracting the sepsis-induced inflammation and organ dysfunction. |
| first_indexed | 2024-04-11T11:01:35Z |
| format | Article |
| id | doaj.art-1c55e496fa97413c9846216878568c2f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-11T11:01:35Z |
| publishDate | 2022-09-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-1c55e496fa97413c9846216878568c2f2022-12-22T04:28:36ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-09-011310.3389/fimmu.2022.992614992614ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsisGustavo Ferreira Alves0Ian Stoppa1Eleonora Aimaretti2Chiara Monge3Raffaella Mastrocola4Elisa Porchietto5Giacomo Einaudi6Debora Collotta7Ilaria Bertocchi8Elena Boggio9Casimiro Luca Gigliotti10Nausicaa Clemente11Manuela Aragno12Daniel Fernandes13Carlo Cifani14Christoph Thiemermann15Chiara Dianzani16Umberto Dianzani17Massimo Collino18Department of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyPharmacology Unit, School of Pharmacy, University of Camerino, Camerino, ItalyPharmacology Unit, School of Pharmacy, University of Camerino, Camerino, ItalyDepartment of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, ItalyDepartment of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDepartment of Clinical and Biological Sciences, University of Turin, Turin, ItalyDepartment of Pharmacology, Federal University of Santa Catarina, Florianópolis, BrazilPharmacology Unit, School of Pharmacy, University of Camerino, Camerino, ItalyWilliam Harvey Research Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, London, United KingdomDepartment of Drug Science and Technology, University of Turin, Turin, ItalyDepartment of Health Sciences, Università del Piemonte Orientale, Novara, ItalyDepartment of Neurosciences (Rita Levi Montalcini), University of Turin, Turin, ItalyInducible T cell co-stimulator (ICOS), an immune checkpoint protein expressed on activated T cells and its unique ligand, ICOSL, which is expressed on antigen-presenting cells and non-hematopoietic cells, have been extensively investigated in the immune response. Recent findings showed that a soluble recombinant form of ICOS (ICOS-Fc) can act as an innovative immunomodulatory drug as both antagonist of ICOS and agonist of ICOSL, modulating cytokine release and cell migration to inflamed tissues. Although the ICOS-ICOSL pathway has been poorly investigated in the septic context, a few studies have reported that septic patients have reduced ICOS expression in whole blood and increased serum levels of osteopontin (OPN), that is another ligand of ICOSL. Thus, we investigated the pathological role of the ICOS-ICOSL axis in the context of sepsis and the potential protective effects of its immunomodulation by administering ICOS-Fc in a murine model of sepsis. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP) in five-month-old male wild-type (WT) C57BL/6, ICOS-/-, ICOSL-/- and OPN-/- mice. One hour after the surgical procedure, either CLP or Sham (control) mice were randomly assigned to receive once ICOS-Fc, F119SICOS-Fc, a mutated form uncapable to bind ICOSL, or vehicle intravenously. Organs and plasma were collected 24 h after surgery for analyses. When compared to Sham mice, WT mice that underwent CLP developed within 24 h a higher clinical severity score, a reduced body temperature, an increase in plasma cytokines (TNF-α, IL-1β, IL-6, IFN-γ and IL-10), liver injury (AST and ALT) and kidney (creatinine and urea) dysfunction. Administration of ICOS-Fc to WT CLP mice reduced all of these abnormalities caused by sepsis. Similar beneficial effects were not seen in CLP-mice treated with F119SICOS-Fc. Treatment of CLP-mice with ICOS-Fc also attenuated the sepsis-induced local activation of FAK, P38 MAPK and NLRP3 inflammasome. ICOS-Fc seemed to act at both sides of the ICOS-ICOSL interaction, as the protective effect was lost in septic knockout mice for the ICOS or ICOSL genes, whereas it was maintained in OPN knockout mice. Collectively, our data show the beneficial effects of pharmacological modulation of the ICOS-ICOSL pathway in counteracting the sepsis-induced inflammation and organ dysfunction.https://www.frontiersin.org/articles/10.3389/fimmu.2022.992614/fullsepsisinflammationICOS (inducible co-stimulatory molecule)cecal ligation and punctureosteopontin (OPN) |
| spellingShingle | Gustavo Ferreira Alves Ian Stoppa Eleonora Aimaretti Chiara Monge Raffaella Mastrocola Elisa Porchietto Giacomo Einaudi Debora Collotta Ilaria Bertocchi Elena Boggio Casimiro Luca Gigliotti Nausicaa Clemente Manuela Aragno Daniel Fernandes Carlo Cifani Christoph Thiemermann Chiara Dianzani Umberto Dianzani Massimo Collino ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis Frontiers in Immunology sepsis inflammation ICOS (inducible co-stimulatory molecule) cecal ligation and puncture osteopontin (OPN) |
| title | ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| title_full | ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| title_fullStr | ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| title_full_unstemmed | ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| title_short | ICOS-Fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| title_sort | icos fc as innovative immunomodulatory approach to counteract inflammation and organ injury in sepsis |
| topic | sepsis inflammation ICOS (inducible co-stimulatory molecule) cecal ligation and puncture osteopontin (OPN) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.992614/full |
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