Specific calcineurin targeting in macrophages confers resistance to inflammation via MKP-1 and p38

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. Synopsis Targeting of calcineurin in macrophages unveils their anti‐inflammatory activity, which bears significant potential for therapeutic exploitation. Calcineurin deletion or inhibition with LxVP peptide, but not the immunosuppressive drugs CsA or FK506, induces anti‐inflammatory macrophages. p38 activity mediates the anti‐inflammatory activation induced by specific calcineurin targeting in macrophages. Calcineurin targeting releases p38 from MKP‐1‐mediated repression. In gene or cell therapy approaches, specific calcineurin targeting in macrophages confers resistance to inflammation associated with arthritis and contact hypersensitivity. Graphical Abstract Targeting of calcineurin in macrophages unveils their anti‐inflammatory activity, which bears significant potential for therapeutic exploitation.