The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice.

Abstract

Chemokines coordinate lung inflammation and fibrosis by acting on chemokine receptors expressed on leukocytes and other cell types. Atypical chemokine receptors (ACKRs) bind, internalize, and degrade chemokines, tuning homeostasis and immune responses. ACKR2 recognizes and decreases the levels of inflammatory CC chemokines. The role of ACKR2 in fibrogenesis is unknown. The purpose of the study was to investigate the role of ACKR2 in the context of pulmonary fibrosis. The effects of ACKR2 expression and deficiency during inflammation and fibrosis were analyzed using a bleomycin-model of fibrosis, ACKR2-deficient mice, bone marrow chimeras, and antibody-mediated leukocyte depletion. ACKR2 was upregulated acutely in response to bleomycin and normalized over time. ACKR2-/- mice showed reduced lethality and lung fibrosis. Bone marrow chimeras showed that lethality and fibrosis depended on ACKR2 expression in pulmonary resident (nonhematopoietic) cells but not on leukocytes. ACKR2-/- mice exhibited decreased expression of tissue-remodeling genes, reduced leukocyte influx, pulmonary injury, and dysfunction. ACKR2-/- mice had early increased levels of CCL5, CCL12, CCL17, and IFNγ and an increased number of CCR2+ and CCR5+ IFNγ-producing γδT cells in the airways counterbalanced by low Th17-lymphocyte influx. There was reduced accumulation of IFNγ-producing γδT cells in CCR2-/- and CCR5-/- mice. Moreover, depletion of γδT cells worsened the clinical symptoms induced by bleomycin and reversed the phenotype of ACKR2-/- mice exposed to bleomycin. ACKR2 controls the CC chemokine expression that drives the influx of CCR2+ and CCR5+ IFNγ-producing γδT cells, tuning the Th17 response that mediated pulmonary fibrosis triggered by bleomycin instillation.

• Authors: Remo C Russo, Benedetta Savino, Massimiliano Mirolo, Chiara Buracchi, Giovanni Germano, Achille Anselmo, Luca Zammataro, Fabio Pasqualini, Alberto Mantovani, Massimo Locati, Mauro M Teixeira
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 314 Issue 6 Pg. L1010-L1025 (06 01 2018) ISSN: 1522-1504 [Electronic] United States
• PMID: 29469612 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCR5 protein, mouse
• Ccr2 protein, mouse
• Chemokines
• IFNG protein, mouse
• Receptors, Antigen, T-Cell, gamma-delta
• Receptors, CCR2
• Receptors, CCR5
• Bleomycin
• Interferon-gamma

Topics

• Animals
• Bleomycin (adverse effects, pharmacology)
• Chemokines (genetics, immunology)
• Interferon-gamma (genetics, immunology)
• Mice
• Mice, Knockout
• Pulmonary Fibrosis (chemically induced, genetics, immunology, pathology)
• Receptors, Antigen, T-Cell, gamma-delta (genetics, immunology)
• Receptors, CCR2 (genetics, immunology)
• Receptors, CCR5 (genetics, immunology)
• Th17 Cells (immunology, pathology)