CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia

Dharmesh V Hirani; Florian Thielen; Siavash Mansouri; Soula Danopoulos; Christina Vohlen; Pinar Haznedar-Karakaya; Jasmine Mohr; Rebecca Wilke; Jaco Selle; Thomas Grosch; Ivana Mizik; Margarete Odenthal; Cristina M Alvira; Celien Kuiper-Makris; Gloria S Pryhuber; Christian Pallasch; S van Koningsbruggen-Rietschel; Denise Al-Alam; Werner Seeger; Rajkumar Savai; Jörg Dötsch; Miguel A Alejandre Alcazar

doi:10.1186/s41232-023-00301-6

CXCL10 deficiency limits macrophage infiltration, preserves lung matrix, and enables lung growth in bronchopulmonary dysplasia

Inflamm Regen. 2023 Oct 24;43(1):52. doi: 10.1186/s41232-023-00301-6.

Authors

Dharmesh V Hirani^#^{1

2}, Florian Thielen^#¹, Siavash Mansouri³, Soula Danopoulos⁴, Christina Vohlen^{1

2

5}, Pinar Haznedar-Karakaya¹, Jasmine Mohr¹, Rebecca Wilke¹, Jaco Selle¹, Thomas Grosch¹, Ivana Mizik¹, Margarete Odenthal^{6

7}, Cristina M Alvira⁸, Celien Kuiper-Makris^{1

6}, Gloria S Pryhuber⁹, Christian Pallasch¹⁰, S van Koningsbruggen-Rietschel⁵, Denise Al-Alam⁴, Werner Seeger^{2

3}, Rajkumar Savai^{2

3}, Jörg Dötsch⁵, Miguel A Alejandre Alcazar^{11

12

13

14}

Affiliations

¹ Department of Pediatric and Adolescent Medicine, Translational Experimental Pediatrics, Experimental Pulmonology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Kerpener Strasse 62, Cologne, 50937, Germany.
² Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Institute for Lung Health (ILH) and Cardio-Pulmonary Institute (CPI), Gießen, Germany.
³ Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Bad Nauheim, Germany.
⁴ Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA.
⁵ Department of Pediatric and Adolescent Medicine, Faculty of Medicine, University Hospital Cologne, and University of Cologne, Cologne, Germany.
⁶ Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany.
⁷ Institute for Pathology, University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany.
⁸ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Department of Pediatrics, Division of Neonatology, University of Rochester Medical Center, Rochester, NY, USA.
¹⁰ Department I of Internal Medicine, Center for Integrated Oncology (CIO) Köln-Bonn, University of Cologne, Cologne, Germany.
¹¹ Department of Pediatric and Adolescent Medicine, Translational Experimental Pediatrics, Experimental Pulmonology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Kerpener Strasse 62, Cologne, 50937, Germany. miguel.alejandre-alcazar@uk-koeln.de.
¹² Universities of Giessen and Marburg Lung Center (UGMLC), member of the German Center for Lung Research (DZL), Institute for Lung Health (ILH) and Cardio-Pulmonary Institute (CPI), Gießen, Germany. miguel.alejandre-alcazar@uk-koeln.de.
¹³ Center for Molecular Medicine Cologne (CMMC), University Hospital Cologne, Faculty of Medicine, and University of Cologne, Cologne, Germany. miguel.alejandre-alcazar@uk-koeln.de.
¹⁴ Cologne Excellence Cluster On Stress Responses in Aging-Associated Diseases (CECAD), University Hospital of Cologne, University of Cologne, Cologne, Germany. miguel.alejandre-alcazar@uk-koeln.de.

^# Contributed equally.

Abstract

Preterm infants with oxygen supplementation are at high risk for bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease. Inflammation with macrophage activation is central to the pathogenesis of BPD. CXCL10, a chemotactic and pro-inflammatory chemokine, is elevated in the lungs of infants evolving BPD and in hyperoxia-based BPD in mice. Here, we tested if CXCL10 deficiency preserves lung growth after neonatal hyperoxia by preventing macrophage activation. To this end, we exposed Cxcl10 knockout (Cxcl10^-/-) and wild-type mice to an experimental model of hyperoxia (85% O₂)-induced neonatal lung injury and subsequent regeneration. In addition, cultured primary human macrophages and murine macrophages (J744A.1) were treated with CXCL10 and/or CXCR3 antagonist. Our transcriptomic analysis identified CXCL10 as a central hub in the inflammatory network of neonatal mouse lungs after hyperoxia. Quantitative histomorphometric analysis revealed that Cxcl10^-/- mice are in part protected from reduced alveolar. These findings were related to the preserved spatial distribution of elastic fibers, reduced collagen deposition, and protection from macrophage recruitment/infiltration to the lungs in Cxcl10^-/- mice during acute injury and regeneration. Complimentary, studies with cultured human and murine macrophages showed that hyperoxia induces Cxcl10 expression that in turn triggers M1-like activation and migration of macrophages through CXCR3. Finally, we demonstrated a temporal increase of macrophage-related CXCL10 in the lungs of infants with BPD. In conclusion, our data demonstrate macrophage-derived CXCL10 in experimental and clinical BPD that drives macrophage chemotaxis through CXCR3, causing pro-fibrotic lung remodeling and arrest of alveolarization. Thus, targeting the CXCL10-CXCR3 axis could offer a new therapeutic avenue for BPD.

Keywords: Bronchopulmonary dysplasia; CXCL10; Collagen; Elastic fibers; Hyperoxia; Lung matrix remodeling.

Abstract

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