TY - JOUR
T1 - The atypical chemokine receptor ACKR2 drives pulmonary fibrosis by tuning influx of CCR2+ and CCR5+ IFNγ-producing γδT cells in mice
AU - Russo, Remo C.
AU - Savino, Benedetta
AU - Mirolo, Massimiliano
AU - Buracchi, Chiara
AU - Germano, Giovanni
AU - Anselmo, Achille
AU - Zammataro, Luca
AU - Pasqualini, Fabio
AU - Mantovani, Alberto
AU - Locati, Massimo
AU - Teixeira, Mauro M.
N1 - Funding Information:
This investigation received financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil) SWE Program under CNPq Grant Agreement No. 201489/2007-4, Edital Universal 14/2011 under CNPq Grant Agreement No. 476071/2011-9, Edital Universal 01/2016 under CNPq Grant Agreement No. 422260/2016-9, and a collaborative grant from CNPq and Italian Foreign Affair Ministry (General Direction for Cultural Cooperation and Promotion, Italy); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil); Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG/Brazil); Pró-Reitoria de Pesquisa da UFMG/EDITAL PRPq–02/2018; European Union Sixth Framework Program (FP6-2005/2010, INNOCHEM consortium–Innovative Chemokine-based Therapeutic Strategies for Autoimmunity and Chronic Inflammation) under Grant Agreement No. LSHBCT2005518167); and European Union Seventh Framework Program (FP7-2007/2013, TIMER consortium) under Grant Agreement No. HEALTH-F4-2011-281608.
Funding Information:
This investigation received financial support from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Brazil) SWE Program under CNPq Grant Agreement No. 201489/2007-4, Edital Universal 14/2011 under CNPq Grant Agreement No. 476071/2011-9, Edital Universal 01/2016 under CNPq Grant Agreement No. 422260/2016-9, and a collaborative grant from CNPq and Italian Foreign Affair Ministry (General Direction for Cultural Cooperation and Promotion, Italy); Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES/Brazil); Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG/Brazil); Pró-Reitoria de Pesquisa da UFMG/EDITAL PRPq-02/2018; European Union Sixth Framework Program (FP6-2005/2010, INNOCHEM consortium-Innovative Chemokine-based Therapeutic Strategies for Autoimmunity and Chronic Inflammation) under Grant Agreement No. LSHBCT2005518167); and European Union Seventh Framework Program (FP7-2007/2013, TIMER consortium) under Grant Agreement No. HEALTH-F4-2011-281608.
Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.
PY - 2018/6
Y1 - 2018/6
N2 - 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.
AB - 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.
KW - ACKR2
KW - Chemokine
KW - Interferon-γ
KW - Pulmonary fibrosis
KW - γδT lymphocytes
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UR - http://www.scopus.com/inward/citedby.url?scp=85048222555&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00233.2017
DO - 10.1152/ajplung.00233.2017
M3 - Article
C2 - 29469612
AN - SCOPUS:85048222555
SN - 1040-0605
VL - 314
SP - L1010-L1025
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 6
ER -