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The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression

Abstract

The mitogen-activated protein kinase p38 mediates cellular responses to injurious stress and immune signaling. Among the many p38 isoforms, p38α is the most widely expressed in adult tissues and can be targeted by various pharmacological inhibitors. Here we investigated how p38α activation is linked to cell type–specific outputs in mouse models of cutaneous inflammation. We found that both myeloid and epithelial p38α elicit inflammatory responses, yet p38α signaling in each cell type served distinct inflammatory functions and varied depending on the mode of skin irritation. In addition, myeloid p38α limited acute inflammation via activation of anti-inflammatory gene expression dependent on mitogen- and stress-activated kinases. Our results suggest a dual function for p38α in the regulation of inflammation and show mixed potential for its inhibition as a therapeutic strategy.

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Figure 1: Disruption of Mapk14 results in efficient removal of its product p38α in myeloid and epithelial cells.
Figure 2: Myeloid p38α signaling is essential for chronic inflammation and acanthosis.
Figure 3: UVB-induced inflammatory infiltration and injury depend on epithelial p38α signaling.
Figure 4: Myeloid p38α acts to limit edema formation in epidermal injury and irritation.
Figure 5: Transcriptional induction of specific genes in LPS-treated macrophages requires p38α.
Figure 6: Signaling by p38α limits the activation of Erk and Jnk.
Figure 7: Transcriptional induction of a subset of p38α target genes depends on MSKs.

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Acknowledgements

We thank S. Krane (Massachusetts General Hospital) for the MMP-13-specific antibody and advice on its use; D. Ginsburg (University of Michigan School of Medicine) for the PAI-2-specific antibody; R. Bravo (Bristol-Myers Squibb Pharmaceutical Research Institute) and C. Caelles (Institute for Research in Biomedicine, Barcelona) for Dusp1-KO mice; and M. Karin for discussion about Jnk-activation mechanisms in p38α-deficient cells. Supported by the Cutaneous Biology Research Center through the Massachusetts General Hospital–Shiseido Agreement (J.M.P.), the US National Institutes of Health (DK043351 to D. Podolsky) and the Center for the Study of Inflammatory Bowel Disease at Massachusetts General Hospital (J.M.P.).

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Correspondence to Jin Mo Park.

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Kim, C., Sano, Y., Todorova, K. et al. The kinase p38α serves cell type–specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol 9, 1019–1027 (2008). https://doi.org/10.1038/ni.1640

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