IKKbeta/NF-kappaB and the miscreant macrophage

Abstract

Macrophage activation relies on complex intracellular signaling processes that integrate the need for rapid inflammatory responses to pathogens with the need to resolve inflammation without permanent harm to normal tissues. Patterns of aberrant macrophage activation characterize and sustain disorders of chronic inflammation, infection, and cancer. New studies now show a role for the NF-kappaB activator IKKbeta in promoting an alternative, immunosuppressive pattern of macrophage activation, which limits the cell's tumoricidal and bactericidal capacities. As cancers and pathogens may have evolved multiple mechanisms to manipulate macrophages for their own survival, is there anything we can do about it?

Figure 1.

IKKβ/NF-κB signals suppress M1-type macrophage activation and promote M2-type activation. Activation of the IKK complex (e.g., in response to TLR- or IL-1–mediated signals) leads to phosphorylation of IκB, triggering its proteasomal degradation. IκB degradation frees NF-κB to translocate to the nucleus and drive the expression of proinflammatory genes. In the context of tumors or infections, IKKβ-induced signals can block STAT-1 activation, which is required for macrophages to acquire a protective M1 phenotype. Deletion of IKKβ in macrophages increases STAT-1 activation and promotes a shift toward the M1 phenotype, with increased production of IL-12 and iNOS and enhanced clearance of tumors and bacterial infections. IKKβ/NF-κB also induces the expression of HIF-1α during hypoxia, linking the evolutionarily ancient signaling pathways of innate immunity and the hypoxic response.