Chapter 29 : Coordinated Regulation of Signaling Pathways during Macrophage Activation

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NF-κB is the prototypical proinflammatory transcription factor and plays an important role in production of cytokines, chemokines, and other proinflammatory mediators during the inflammatory response ( ). NF-κB activation in macrophages is best characterized in response to proinflammatory cytokines, such as tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β), or the recognition of microbial products by Toll-like receptors (TLRs) or NOD-like receptors (NLRs). Using various upstream signaling pathways, these receptors converge on activation of the IKK (IκB kinase) complex, leading to activation of NF-κB. The IKK complex consists of two kinase subunits, IKKα (CHUK) and IKKβ (IKBKB), and the ubiquitin-binding protein IKKγ (IKBKG) ( ). Despite its well-established role as a proinflammatory transcription factor in many cells, the NF-κB pathway in macrophages also has important anti-inflammatory roles ( ). This was revealed by studies using the targeted deletion of IKKβ in macrophages, which was shown to have proinflammatory effects in several models of inflammation ( ).

Citation: Lawrence T. 2017. Coordinated Regulation of Signaling Pathways during Macrophage Activation, p 543-552. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0025-2015
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Figure 1

Cross talk between signaling pathways in macrophages during encounters with microbial stimuli. Macrophages express a number of receptors that can recognize microbial patterns, including TLRs and phagocytic receptors. In addition, cytosolic detectors such as inflammasomes can respond to microbes that invade the cytoplasm of cells or escape the phagocytic compartment. TLRs directly trigger activation of NF-κB, through the IKK complex and MAPK pathways, to drive proinflammatory and anti-inflammatory cytokine expression. Endosomal TLR signaling also activates the TBK1 (TANK-binding kinase 1)-dependent expression of type I IFN (IFN-I) through triggering of IRF activation. Cytokines such as IFN-I, IL-6, and IL-10 can also trigger autocrine signaling through JAK/STAT activation, whereas other proinflammatory cytokines such as TNF-α and IL-1β activate IKK and MAPK pathways. There are a number of mechanisms for negative (red) and positive (green) cross talk between these signaling pathways in macrophages to fine-tune the magnitude and duration of their activation.

Citation: Lawrence T. 2017. Coordinated Regulation of Signaling Pathways during Macrophage Activation, p 543-552. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0025-2015
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