Proposed model for p38α in myeloid cell cytokine response to systemic lipopolysaccharide (LPS). (A) In wild-type (WT) mice, myeloid cells respond to systemic LPS by producing an acute phase response, including the production of proinflammatory cytokines, as well as the anti-inflammatory cytokine IL-10. The systemic response spreads to the brain where microglia produce cytokines locally in the CNS. (B) In the p38αΔLysM-Cre knockout (KO) mice, the systemic acute phase response is suppressed such that there is less proinflammatory cytokine production in the blood. However, there is also a loss of the negative feedback provided by the anti-inflammatory IL-10, which we propose leads to an exaggerated acute proinflammatory cytokine response in the CNS.