Mitogen-activated Protein Kinases in Innate Immunity

Key Points Mitogen-activated protein kinases (MAPKs) in innate immune cells are activated by a range of pattern recognition receptors, of which the best studied are Toll-like receptors (TLRs). TLR ligation induces the formation of a signalling complex that includes IL-1R-associated kinases (IRAKs) and TNFR-associated factor 6 (TRAF6), which is mediated by K63-linked polyubiquitylation. This complex interacts with and activates TGFβ-activated kinase 1 (TAK1), a MAPK kinase kinase (MAP3K) upstream of p38α and Jun N-terminal kinases (JNKs). TAK1 can also activate the IκB kinase (IKK) complex, leading to the activation of the transcription factor nuclear factor-κB and the MAP3K tumour progression locus 2 (TPL2), which is upstream of extracellular signal-regulated kinase 1 (ERK1) and ERK2. Recent genetic evidence, however, has shown that TAK1 is not required for TLR activation of MAPKs in primary macrophages, and the MAP3K involved remains to be identified. MAPK signalling has several of roles in innate immune responses, ranging from the induction of pro-inflammatory mediators, such as cytokines and chemokines, to the activation of anti-inflammatory feedback pathways. MAPKs can activate downstream kinases that have crucial roles in immunity; for example, p38α activates MAPK-activated protein kinase 2 (MK2), which promotes tumour necrosis factor (TNF) production. By contrast, the activation of mitogen- and stress-activated kinases (MSKs) by p38α or by ERK1 and ERK2 results in the increased transcription of the anti-inflammatory cytokines interleukin-10 (IL-10) and IL-1 receptor antagonist (IL-1RA). MAPK signalling induces the expression of dual specificity phosphatases (DUSPs). This establishes a negative feedback loop, in which the DUSPs dephosphorylate and inactivate MAPKs. Genetic studies have shown the crucial role of DUSPs in controlling innate immune responses. Bacterial pathogens have evolved ways to directly target MAPKs to downregulate the host immune response; for example, distinct bacterial proteins have been shown to inhibit MAPK signalling by inactivating MAPK kinase (MKK) enzymes and by activating DUSPs. Small-molecule inhibitors which target MAPK signalling have the potential to function as anti-inflammatory drugs. p38 inhibitors were the first MAPK inhibitors to be developed, but clinical results from using these compounds have been disappointing. As a result, focus in the pharmaceutical industry has shifted to targeting upstream MAP3Ks or downstream kinases, such as MK2.