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

Abstract

Acute inflammatory activation of macrophages by Toll-like and related receptors is characterized by transient activation of MAPK-, NF-κB- 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.

Figure 1

(A) Acute macrophage activation. Core inflammatory signaling downstream of activating receptors that is mediated by MAPKs, NF-κB and IRFs activates inflammatory gene expression by inducing transcription factors to bind to inflammatory gene loci, chromatin modifications such as acetylation (Ac) or trimethylation (Me3) of histones, and dismissal of transcriptional repressors such as NCoR. At the same time, the core inflammatory signals induce feedback inhibition mechanisms that restrain the magnitude of activation and terminate the acute phase of signaling and gene expression. Feedback inhibition is mediated by signaling inhibitors including IκBa, SOCS1 and A20, and transcriptional repressors including STAT3 and ATF-3. (B) Transition to tolerance and alternative activation. Several hours after strong activation as depicted in (A), upon rechallenge with the same activating stimuli inflammatory signaling by MAPKs, NF-κB and IRFs is suppressed by signaling inhibitors that include A20, IRAK-M, and SHIP. In addition, chromatin at inflammatory gene loci assumes a repressive configuration, including diminished acetylation and methylation of select histone lysine residues. Expression of nontolerized genes is maintained and further induced by inflammatory stimulation. Mechanisms regulating expression of nontolerized genes are not well understood, but appear to involve low-level core inflammatory signals (MAPKs), alternative signaling pathways (GSK3, p50) and permissive chromatin remodeling.

Figure 2

Differentiation of monocytes and macrophages after trafficking into inflammatory sites. Monocytes that enter inflammatory sites and are strongly activated by TLRs, TNFRs or ITAM-associated receptors will enter an acute inflammatory state (M1) and can also differentiate into inflammatory DCs. Cytokines such as IFN-γ and GM-CSF will maintain the inflammatory state. With time and migration through inflamed tissues, inflammatory monocytes/macrophages transition to tolerant alternatively activated (Tol/Alt A) states. At alternative inflammatory sites characterized by M2 cytokine expression monocytes can directly transition to alternatively activated states (not depicted).