title: Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38.
abstract: Macrophages contribute to tissue homeostasis and influence inflammatory responses by modulating their phenotype in response to the local environment. Understanding the molecular mechanisms governing this plasticity would open new avenues for the treatment for inflammatory disorders. We show that deletion of calcineurin (CN) or its inhibition with LxVP peptide in macrophages induces an anti-inflammatory population that confers resistance to arthritis and contact hypersensitivity. Transfer of CN-targeted macrophages or direct injection of LxVP-encoding lentivirus has anti-inflammatory effects in these models. Specific CN targeting in macrophages induces p38 MAPK activity by downregulating MKP-1 expression. However, pharmacological CN inhibition with cyclosporin A (CsA) or FK506 did not reproduce these effects and failed to induce p38 activity. The CN-inhibitory peptide VIVIT also failed to reproduce the effects of LxVP. p38 inhibition prevented the anti-inflammatory phenotype of CN-targeted macrophages, and mice with defective p38-activation were resistant to the anti-inflammatory effect of LxVP. Our results identify a key role for CN and p38 in the modulation of macrophage phenotype and suggest an alternative treatment for inflammation based on redirecting macrophages toward an anti-inflammatory status.
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Escolano
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Martínez-Martínez
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Área de Biología Celular y del Desarrollo, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Arántzazu
authors.initials: A
authors.lastname: Alfranca
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Katia
authors.initials: K
authors.lastname: Urso
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Helena M
authors.initials: HM
authors.lastname: Izquierdo
authors.affiliation: Instituto de Parasitología y Biomedicina "López-Neyra", CSIC, Granada, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Delgado
authors.affiliation: Human DNA variability Department and Oncology Department, Pfizer-Universidad de Granada-Junta de Andalucía Centre for Genomics and Oncological Research (GENYO), Granada, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Martín
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Sabio
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sancho
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain Departamento de Biología Molecular, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Gómez-del Arco
authors.affiliation: Departamento de Biología Vascular e Inflamación, Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain jmredondo@cnic.es.
authors.forename: Juan Miguel
authors.initials: JM
authors.lastname: Redondo
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D002478:Cells, Cultured; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010587:Phagocytosis / Q000235:genetics / Q000502:physiology; D060888:Real-Time Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D048051:p38 Mitogen-Activated Protein Kinases; D019703:Calcineurin; D054638:Dual Specificity Phosphatase 1
keywords: anti‐inflammatory therapy; calcineurin; inflammation; macrophage; p38 MAPK