Macrophages and the Recovery from Acute and Chronic Inflammation

Abstract

In recent years, researchers have devoted much attention to the diverse roles of macrophages and their contributions to tissue development, wound healing, and angiogenesis. What should not be lost in the discussions regarding the diverse biology of these cells is that when perturbed, macrophages are the primary contributors to potentially pathological inflammatory processes. Macrophages stand poised to rapidly produce large amounts of inflammatory cytokines in response to danger signals. The production of these cytokines can initiate a cascade of inflammatory mediator release that can lead to wholesale tissue destruction. The destructive inflammatory capability of macrophages is amplified by exposure to exogenous interferon-γ, which prolongs and heightens inflammatory responses. In simple terms, macrophages can thus be viewed as incendiary devices with hair triggers waiting to detonate. We have begun to ask questions about how these cells can be regulated to mitigate the collateral destruction associated with macrophage activation.

Keywords: NF-κB; TLR; adenosine; cytokines; prostaglandin; transcription.

Figure 1

Inflammation can be negatively regulated by a multitude of cellular molecules and mechanisms. The initiation of TLR signaling pathways leading to inflammation can be negatively regulated at various levels from ligand binding to transcription. Whereas primary or secondary signaling through certain GPCRs, nuclear receptors, or inhibitory receptors can cross-regulate the inflammatory pathways, cellular mechanisms such as epigenetic regulation, ubiquitination, and cell death can operate at both micro- and macrolevels to inhibit inflammation in macrophages. Such receptor-mediated signaling pathways and cellular mechanisms can give rise to anti-inflammatory cytokines that can mitigate proinflammatory cytokines; transcription factors that turn on mRNA transcription of anti-inflammatory molecules; and microRNAs that mediate post-transcriptional silencing of mRNAs encoding inflammatory proteins. Abbreviations: CYLD, cylindromatosis; ER, endoplasmic reticulum; FcγR, Fcγ receptor; GPCR, G-protein coupled receptor; IFN-α, interferon-α; IL, interleukin; LYP, lymphocyte tyrosine phosphatase; PPARγ, peroxisome proliferator-activated receptor γ; TGF-β, transforming growth factor-β; TLR, Toll-like receptor.