CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis

Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to re...

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Autores principales:	Laetitia Pouzol, Anna Sassi, Nadège Baumlin, Mélanie Tunis, Daniel S. Strasser, François Lehembre, Marianne M. Martinic
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	acute lung injury acute respiratory distress syndrome immunomodulation CXCR7 CXCR3 CXCR4 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/87143f960dcd406b842cdbeee31d0c1a
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spelling	oai:doaj.org-article:87143f960dcd406b842cdbeee31d0c1a2021-11-05T07:29:34ZCXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis1663-981210.3389/fphar.2021.748740https://doaj.org/article/87143f960dcd406b842cdbeee31d0c1a2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.748740/fullhttps://doaj.org/toc/1663-9812Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.Laetitia PouzolAnna SassiNadège BaumlinMélanie TunisDaniel S. StrasserFrançois LehembreMarianne M. MartinicFrontiers Media S.A.articleacute lung injuryacute respiratory distress syndromeimmunomodulationCXCR7CXCR3CXCR4Therapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acute lung injury acute respiratory distress syndrome immunomodulation CXCR7 CXCR3 CXCR4 Therapeutics. Pharmacology RM1-950
spellingShingle	acute lung injury acute respiratory distress syndrome immunomodulation CXCR7 CXCR3 CXCR4 Therapeutics. Pharmacology RM1-950 Laetitia Pouzol Anna Sassi Nadège Baumlin Mélanie Tunis Daniel S. Strasser François Lehembre Marianne M. Martinic CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
description	Loss of control in the trafficking of immune cells to the inflamed lung tissue contributes to the pathogenesis of life-threatening acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS). Targeting CXCR7 has been proposed as a potential therapeutic approach to reduce pulmonary inflammation; however, its role and its crosstalk with the two chemokine receptors CXCR3 and CXCR4 via their shared ligands CXCL11 and CXCL12 is not yet completely understood. The present paper aimed to characterize the pathological role of the CXCR3/CXCR4/CXCR7 axis in a murine model of ALI. Lipopolysaccharide (LPS) inhalation in mice resulted in the development of key pathologic features of ALI/ARDS, including breathing dysfunctions, alteration in the alveolar capillary barrier, and lung inflammation. LPS inhalation induced immune cell infiltration into the bronchoalveolar space, including CXCR3+ and CXCR4+ cells, and enhanced the expression of the ligands of these two chemokine receptors. The first-in-class CXCR7 antagonist, ACT-1004-1239, increased levels of CXCL11 and CXCL12 in the plasma without affecting their levels in inflamed lung tissue, and consequently reduced CXCR3+ and CXCR4+ immune cell infiltrates into the bronchoalveolar space. In the early phase of lung inflammation, characterized by a massive influx of neutrophils, treatment with ACT-1004-1239 significantly reduced the LPS-induced breathing pattern alteration. Both preventive and therapeutic treatment with ACT-1004-1239 reduced lung vascular permeability and decreased inflammatory cell infiltrates. In conclusion, these results demonstrate a key pathological role of CXCR7 in ALI/ARDS and highlight the clinical potential of ACT-1004-1239 in ALI/ARDS pathogenesis.
format	article
author	Laetitia Pouzol Anna Sassi Nadège Baumlin Mélanie Tunis Daniel S. Strasser François Lehembre Marianne M. Martinic
author_facet	Laetitia Pouzol Anna Sassi Nadège Baumlin Mélanie Tunis Daniel S. Strasser François Lehembre Marianne M. Martinic
author_sort	Laetitia Pouzol
title	CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
title_short	CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
title_full	CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
title_fullStr	CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
title_full_unstemmed	CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis
title_sort	cxcr7 antagonism reduces acute lung injury pathogenesis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/87143f960dcd406b842cdbeee31d0c1a
work_keys_str_mv	AT laetitiapouzol cxcr7antagonismreducesacutelunginjurypathogenesis AT annasassi cxcr7antagonismreducesacutelunginjurypathogenesis AT nadegebaumlin cxcr7antagonismreducesacutelunginjurypathogenesis AT melanietunis cxcr7antagonismreducesacutelunginjurypathogenesis AT danielsstrasser cxcr7antagonismreducesacutelunginjurypathogenesis AT francoislehembre cxcr7antagonismreducesacutelunginjurypathogenesis AT mariannemmartinic cxcr7antagonismreducesacutelunginjurypathogenesis
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CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis

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