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...

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Main Authors:	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
Format:	article
Language:	EN
Published:	Frontiers Media S.A. 2021
Subjects:	macrophages methotrexate pemetrexed sCD14 predictor biomarker Immunologic diseases. Allergy RC581-607
Online Access:	https://doaj.org/article/0c17ff55e2564e3295c528665d899119
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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
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The Macrophage Reprogramming Ability of Antifolates Reveals Soluble CD14 as a Potential Biomarker for Methotrexate Response in Rheumatoid Arthritis

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