CXCR7 Antagonism Reduces Acute Lung Injury Pathogenesis

Abstract

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.

Atypical Roles of the Chemokine Receptor ACKR3/CXCR7 in Platelet Pathophysiology

“…ACKR3/CXCR7 is ubiquitously expressed to various extent by circulating immune (monocytes, macrophages, [ 28 ] T-lymphocytes [ 190 ], B-lymphocytes [ 191 ], neutrophils [ 90 , 91 , 92 ]) and vascular cells (endothelium [ 27 ]) and also cells constituting the organs that these blood vessels perfuse (e.g., myocardium [ 26 ], brain [ 30 , 32 , 192 , 193 ]). Therefore, ACKR3/CXCR7 may elicit a cell- and organ-specific functional response [ 46 ], which cannot be restricted specifically to platelets.…”

“…Neutrophils substantially aggravate HIT-associated thrombotic complications [ 77 ]. Neutrophils express ACKR3/CXCR7 [ 90 , 91 ], the antagonism of which regulates pulmonary injury associated with acute inflammation [ 92 ]. However, we observed that the CXCR7-agonist reduces HIT-IgG-induced human neutrophil activation, particularly the activation of CD11b in the Mac-1 complex.…”

Absorption, Metabolism, and Excretion of ACT-1004-1239, a First-In-Class CXCR7 Antagonist: In Vitro, Preclinical, and Clinical Data

“…ACT-1004-1239 is an orally available, potent, and selective first-in-class CXCR7 antagonist that showed efficacy in preclinical animal models of multiple sclerosis ( Pouzol et al, 2021a ) and acute lung injury ( Pouzol et al, 2021b ), and had a favorable clinical profile following single- ( Huynh et al, 2021b ) and multiple-dose ( Huynh et al, 2021a ) administration. In context of drug development, identification of metabolites and metabolic pathways of a drug is of utmost relevance.…”

“…ACT-1004-1239 is an orally available, potent, selective, insurmountable, small-molecule CXCR7 antagonist ( Richard-Bildstein et al, 2020 ). Preclinically, ACT-1004-1239 showed dose-dependent efficacy in various animal models such as of multiple sclerosis ( Pouzol et al, 2021a ) and acute lung injury ( Pouzol et al, 2021b ) using its ligands CXCL11 and CXCL12 as biomarker of target engagement. Dose-dependent increases in CXCL11 and CXCL12 plasma concentration were associated with a reduction in immune cell infiltrates into the central nervous system ( Pouzol et al, 2021c ) or the bronchoalveolar space ( Pouzol et al, 2021b ).…”

Editorial: Women in drug metabolism and transport: 2021

“…Such integrative approach accelerates clinical development ( Muehlan et al, 2018 ). Huynh et al combine this innovative method with in vitro studies in order to characterize ADME in humans with the use of rat samples for metabolite structure elucidation of major human metabolites, and to identify human enzymes involved in the metabolism of an orally available, promising new drug with proven efficacy in preclinical animal models of multiple sclerosis ( Pouzol et al, 2021a ) and acute lung injury ( Pouzol et al, 2021b ), and favorable clinical profile following single and multiple-dose ( Huynh et al, 2021a ; Huynh et al, 2021b ) administration. Results from their in vitro and in vivo studies highlight the relevance of preclinical investigations in supporting the identification of metabolites in humans, allowing determining potential successive clinical studies.…”