MEK2 Suppresses IL-4 Polarization via PPARγ and Negatively Impacts Macrophage Epithelial Crosstalk to Delay Repair

MEK2 is a highly conserved mitogen-activated protein kinase whose pathway activation is increased in both acute respiratory distress syndrome (ARDS) and murine acute lung injury (ALI). We previously demonstrated that leukocyte-specific Mek2 ^-/- mice have accelerated recovery from ALI, including earlier restoration of alveolar barrier function, indicating that leukocyte MEK2 prolongs lung injury. Here, we tested the hypothesis that MEK2 suppresses reparative IL-4-driven macrophage function. Transcriptional profiling of WT and Mek2 ^-/- bone marrow-derived macrophages (BMDM) revealed that MEK2 inhibits a subset of IL-4-dependent gene expression, including those enriched in wound repair pathways. Mechanistically, MEK2 is required for IL-4-induced ERK1/2 phosphorylation and the suppression of PPARγ levels. Pharmacologic inhibition of PPARγ abolished the enhanced IL-4-dependent gene expression observed in Mek2 ^-/- BMDMs, identifying PPARγ as a key mediator by which MEK2 restrains reparative macrophage polarization. To determine the functional relevance of these findings, we evaluated macrophage-supported alveolar epithelial type II (AT2) cell growth using an alveolar organoid model. IL-4-polarized macrophages enhanced AT2 proliferation in a PPARγ-dependent manner, whereas MEK2 suppressed this reparative effect. Together, these findings identify MEK2 as a negative regulator of reparative macrophage programming via suppression of PPARγ. Targeting MEK2 may represent a novel therapeutic strategy to accelerate repair of lung injury via enhancement of PPARγ activity in reparative macrophages.