p38α senses environmental stress to control innate immune responses via mechanistic target of rapamycin.

The MAPK p38 alpha senses environmental stressors and orchestrates inflammatory and immunomodulatory reactions. However, the molecular mechanism how p38 alpha controls immunomodulatory responses in myeloid cells remains elusive. We found that in monocytes and macrophages, p38 alpha activated the mechanistic target of rapamycin (mTOR) pathway in vitro and in vivo. p38 alpha signaling in myeloid immune cells promoted IL-10 but inhibited IL-12 expression via mTOR and blocked the differentiation of proinflammatory CD4(+) Th1 cells. Cellular stress induced p38 alpha-mediated mTOR activation that was independent of PI3K but dependent on the MAPK-activated protein kinase 2 and on the inhibition of tuberous sclerosis 1 and 2, a negative regulatory complex of mTOR signaling. Remarkably, p38 alpha and PI3K concurrently modulated mTOR to balance IL-12 and IL-10 expression. Our data link p38 alpha to mTOR signaling in myeloid immune cells that is decisive for tuning the immune response in dependence on the environmental milieu. The Journal of Immunology, 2013, 190: 1519-1527.