The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis

The identification of “trained immunity/tolerance” in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeut...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Sara Fuentelsaz-Romero, Celia Barrio-Alonso, Raquel García Campos, Mónica Torres Torresano, Ittai B. Muller, Ana Triguero-Martínez, Laura Nuño, Alejandro Villalba, Rosario García-Vicuña, Gerrit Jansen, María-Eugenia Miranda-Carús, Isidoro González-Álvaro, Amaya Puig-Kröger
Formato: article
Lenguaje:EN
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://doaj.org/article/0c17ff55e2564e3295c528665d899119
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:0c17ff55e2564e3295c528665d899119
record_format dspace
spelling oai:doaj.org-article:0c17ff55e2564e3295c528665d8991192021-11-05T13:13:05ZThe Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis1664-322410.3389/fimmu.2021.776879https://doaj.org/article/0c17ff55e2564e3295c528665d8991192021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.776879/fullhttps://doaj.org/toc/1664-3224The identification of “trained immunity/tolerance” in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA). We have previously showed that MTX promotes trained immunity in human macrophages. In the present manuscript, we have assessed the anti-inflammatory effects of PMX and MTX and found that OCM blockers alter the functional and gene expression profile of human macrophages and that OCM blockade reprograms macrophages towards a state of lipopolysaccharide (LPS) tolerance at the signaling and functional levels. Moreover, OCM blockade reduced macrophage LPS responsiveness by impairing the expression of membrane-bound and soluble CD14 (sCD14). The therapeutic relevance of these results was later confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. As a whole, our results demonstrate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance and positions sCD14 as a valuable tool to predict MTX response in RA patients.Sara Fuentelsaz-RomeroCelia Barrio-AlonsoRaquel García CamposMónica Torres TorresanoIttai B. MullerAna Triguero-MartínezLaura NuñoAlejandro VillalbaRosario García-VicuñaGerrit JansenMaría-Eugenia Miranda-CarúsIsidoro González-ÁlvaroAmaya Puig-KrögerFrontiers Media S.A.articlemacrophagesmethotrexatepemetrexedsCD14predictor biomarkerImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution DOAJ
collection DOAJ
language EN
topic macrophages
methotrexate
pemetrexed
sCD14
predictor biomarker
Immunologic diseases. Allergy
RC581-607
spellingShingle macrophages
methotrexate
pemetrexed
sCD14
predictor biomarker
Immunologic diseases. Allergy
RC581-607
Sara Fuentelsaz-Romero
Celia Barrio-Alonso
Raquel García Campos
Mónica Torres Torresano
Ittai B. Muller
Ana Triguero-Martínez
Laura Nuño
Alejandro Villalba
Rosario García-Vicuña
Gerrit Jansen
María-Eugenia Miranda-Carús
Isidoro González-Álvaro
Amaya Puig-Kröger
The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
description The identification of “trained immunity/tolerance” in myeloid cells has changed our perception of the performance of monocytes and macrophages during inflammatory and immune responses. Pemetrexed (PMX) and methotrexate (MTX) are blockers of the one-carbon metabolism (OCM) and commonly used therapeutic agents in cancer and rheumatoid arthritis (RA). We have previously showed that MTX promotes trained immunity in human macrophages. In the present manuscript, we have assessed the anti-inflammatory effects of PMX and MTX and found that OCM blockers alter the functional and gene expression profile of human macrophages and that OCM blockade reprograms macrophages towards a state of lipopolysaccharide (LPS) tolerance at the signaling and functional levels. Moreover, OCM blockade reduced macrophage LPS responsiveness by impairing the expression of membrane-bound and soluble CD14 (sCD14). The therapeutic relevance of these results was later confirmed in early RA patients, as MTX-responder RA patients exhibit lower sCD14 serum levels, with baseline sCD14 levels predicting MTX response. As a whole, our results demonstrate that OCM is a metabolic circuit that critically mediates the acquisition of innate immune tolerance and positions sCD14 as a valuable tool to predict MTX response in RA patients.
format article
author Sara Fuentelsaz-Romero
Celia Barrio-Alonso
Raquel García Campos
Mónica Torres Torresano
Ittai B. Muller
Ana Triguero-Martínez
Laura Nuño
Alejandro Villalba
Rosario García-Vicuña
Gerrit Jansen
María-Eugenia Miranda-Carús
Isidoro González-Álvaro
Amaya Puig-Kröger
author_facet Sara Fuentelsaz-Romero
Celia Barrio-Alonso
Raquel García Campos
Mónica Torres Torresano
Ittai B. Muller
Ana Triguero-Martínez
Laura Nuño
Alejandro Villalba
Rosario García-Vicuña
Gerrit Jansen
María-Eugenia Miranda-Carús
Isidoro González-Álvaro
Amaya Puig-Kröger
author_sort Sara Fuentelsaz-Romero
title The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
title_short The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
title_full The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
title_fullStr The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
title_full_unstemmed The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis
title_sort macrophage reprogramming ability of antifolates reveals soluble cd14 as a potential biomarker for methotrexate response in rheumatoid arthritis
publisher Frontiers Media S.A.
publishDate 2021
url https://doaj.org/article/0c17ff55e2564e3295c528665d899119
work_keys_str_mv AT sarafuentelsazromero themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT celiabarrioalonso themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT raquelgarciacampos themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT monicatorrestorresano themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT ittaibmuller themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT anatrigueromartinez themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT lauranuno themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT alejandrovillalba themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT rosariogarciavicuna themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT gerritjansen themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT mariaeugeniamirandacarus themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT isidorogonzalezalvaro themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT amayapuigkroger themacrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT sarafuentelsazromero macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT celiabarrioalonso macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT raquelgarciacampos macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT monicatorrestorresano macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT ittaibmuller macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT anatrigueromartinez macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT lauranuno macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT alejandrovillalba macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT rosariogarciavicuna macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT gerritjansen macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT mariaeugeniamirandacarus macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT isidorogonzalezalvaro macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
AT amayapuigkroger macrophagereprogrammingabilityofantifolatesrevealssolublecd14asapotentialbiomarkerformethotrexateresponseinrheumatoidarthritis
_version_ 1718444209375019008