Macrophage activation by endogenous danger signals

Abstract

Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous 'danger signals'. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline-encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti-inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined.

Figure 1. Overview of RIG-I- and MDA5-mediated signalling pathway

Viral ssRNA with 5′-triphosphate group and dsRNA are detected by the cytoplasmic pathogen recognition receptors, RIG-I and MDA5, respectively. Viral RNAs also activate 2′,5′-oligoadenylate synthetase (OAS) to synthesize 2′,5′-linked oligoadenylate (2–5A) from ATP. 2–5A activates RNase L to cleavage cellular RNAs to yield small self-RNA molecules, which are also recognized by RIG-I and/or MDA5. RIG-I and MDA5 contain N-terminal CARD and C-terminal RNA helicase motifs. In addition, RIG-I contains a repressor domain (RD). The RNA-mediated interaction induces conformational changes of RIG-1 and MDA5, which leads to the CARD–CARD interaction of RIG-I and MDA5 with their adaptor, CARD-containing MAVS (also known as VISA, Cardif and IPS-1) in the mitochondrial membrane. These events relay the signal through activation and translocation of NF-κB p65–p50 heterodimer and IRF3 as well as IRF7 into the nucleus to activate downstream genes that encode α- and β-interferon. The exact roles of TRAF2, TRAF6, FADD and RIP1 in this pathway are yet to be defined. Activation of RIG-I by the ubiquitin ligase TRIM25-mediated lysine-63-linked ubiquitination is not shown, neither is a MAVS-mediated MAP kinase cascade. Red arrows indicate phosphorylation