Inflammatory signaling in macrophages: Transitions from acute to tolerant and alternative activation states

Acute inflammatory activation of macrophages by Toll-like and related receptors is characterized by transient activation of MAPK-, NF-kappa B- and IRF-mediated signaling pathways and expression of pro-inflammatory genes. This activation state is inherently unstable and often transitions into a state of 'tolerance' characterized by diminished signaling, repressive chromatin modifications, and an alternative gene expression program. This Viewpoint describes signaling and epigenetic mechanisms associated with transition to tolerant states, which are proposed to correspond to alternative activation states programmed by the original inflammatory stimuli.