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  • Review Article
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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.

Abstract

Following pathogen infection or tissue damage, the stimulation of pattern recognition receptors on the cell surface and in the cytoplasm of innate immune cells activates members of each of the major mitogen-activated protein kinase (MAPK) subfamilies — the extracellular signal-regulated kinase (ERK), p38 and Jun N-terminal kinase (JNK) subfamilies. In conjunction with the activation of nuclear factor-κB and interferon-regulatory factor transcription factors, MAPK activation induces the expression of multiple genes that together regulate the inflammatory response. In this Review, we discuss our current knowledge about the regulation and the function of MAPKs in innate immunity, as well as the importance of negative feedback loops in limiting MAPK activity to prevent host tissue damage. We also examine how pathogens have evolved complex mechanisms to manipulate MAPK activation to increase their virulence. Finally, we consider the potential of the pharmacological targeting of MAPK pathways to treat autoimmune and inflammatory diseases.

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Figure 1: MAPK signalling cascades.
Figure 2: Activation of MAPKs.
Figure 3: Negative feedback control of MAPK signalling by p38α.
Figure 4: DUSP regulation of TLR signalling.

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References

  1. Newton, K. & Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4, a006049 (2012).

    PubMed  PubMed Central  Google Scholar 

  2. Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nature Immunol. 11, 373–384 (2010).

    CAS  Google Scholar 

  3. Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Medzhitov, R. & Horng, T. Transcriptional control of the inflammatory response. Nature Rev. Immunol. 9, 692–703 (2009).

    CAS  Google Scholar 

  5. Tseng, P. H. et al. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nature Immunol. 11, 70–75 (2010).

    CAS  Google Scholar 

  6. Wang, C. et al. TAK1 is a ubiquitin-dependent kinase of MKK and IKK. Nature 412, 346–351 (2001). This is the first study to establish a role for K63-linked ubiquitylation in MAPK signalling.

    CAS  Google Scholar 

  7. Sakurai, H. Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol. Sci. 33, 522–530 (2012).

    CAS  PubMed  Google Scholar 

  8. Ajibade, A. A. et al. TAK1 negatively regulates NF-κB and p38 MAP kinase activation in Gr-1+CD11b+ neutrophils. Immunity 36, 1–12 (2012).

    Google Scholar 

  9. Shim, J. H. et al. TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev. 19, 2668–2681 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Sato, S. et al. Essential function of the kinase TAK1 in innate and adaptive immune responses. Nature Immunol. 6, 1087–1095 (2005). References 8 and 10 highlight the complex cell type-specific roles of TAK1 in MAPK and NF-κB activation by TLRs.

    CAS  Google Scholar 

  11. Mendoza, H. et al. Roles for TAB1 in regulating the IL-1-dependent phosphorylation of the TAB3 regulatory subunit and activity of the TAK1 complex. Biochem. J. 409, 711–722 (2008).

    CAS  PubMed  Google Scholar 

  12. Omori, E., Inagaki, M., Mishina, Y., Matsumoto, K. & Ninomiya-Tsuji, J. Epithelial transforming growth factor β-activated kinase 1 (TAK1) is activated through two independent mechanisms and regulates reactive oxygen species. Proc. Natl Acad. Sci. USA 109, 3365–3370 (2012).

    CAS  PubMed  Google Scholar 

  13. Ori, D. et al. Essential roles of K63-linked polyubiquitin-binding proteins TAB2 and TAB3 in B cell activation via MAPKs. J. Immunol. 190, 4037–4045 (2013).

    CAS  PubMed  Google Scholar 

  14. Eftychi, C., Karagianni, N., Alexiou, M., Apostolaki, M. & Kollias, G. Myeloid TAKL acts as a negative regulator of the LPS response and mediates resistance to endotoxemia. PLoS ONE 7, e31550 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Saraiva, M. & O'Garra, A. The regulation of IL-10 production by immune cells. Nature Rev. Immunol. 10, 170–181 (2010).

    CAS  Google Scholar 

  16. Greten, F. R. et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKK. Cell 130, 918–931 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Matsuzawa, A. et al. ROS-dependent activation of the TRAF6–ASK1–p38 pathway is selectively required for TLR4-mediated innate immunity. Nature Immunol. 6, 587–592 (2005).

    CAS  Google Scholar 

  18. Mnich, S. J. et al. Critical role for apoptosis signal-regulating kinase 1 in the development of inflammatory K/BxN serum-induced arthritis. Int. Immunopharmacol. 10, 1170–1176 (2010).

    CAS  PubMed  Google Scholar 

  19. Noguchi, T. et al. Recruitment of tumor necrosis factor receptor-associated factor family proteins to apoptosis signal-regulating kinase 1 signalosome is essential for oxidative stress-induced cell death. J. Biol. Chem. 280, 37033–37040 (2005).

    CAS  PubMed  Google Scholar 

  20. Fujino, G. et al. Thioredoxin and TRAF family protiens regulate reactive oxygen species-dependent activation of ASK1 through reciprocal modulation of the N-terminal homophilic interactioin of ASK1. Mol. Cell. Biol. 27, 8152–8163 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Noh, K. T., Park, Y. M., Cho, S. G. & Choi, E. J. GSK-3β-induced ASK1 stabilization is crucial in LPS-induced endotoxin shock. Exp. Cell Res. 317, 1663–1668 (2011).

    CAS  PubMed  Google Scholar 

  22. Nakamura, K., Kimple, A. J., Siderovski, D. P. & Johnson, G. L. PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-κB activation. J. Biol. Chem. 285, 2077–2089 (2010).

    CAS  PubMed  Google Scholar 

  23. Huang, Q. et al. Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nature Immunol. 5, 98–103 (2004).

    CAS  Google Scholar 

  24. Kim, K., Duramad, O., Qin, X. F. & Su, B. MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages. Immunology 120, 242–250 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gantke, T., Sriskantharajah, S., Sadowski, M. & Ley, S. C. IκB kinase regulation of the TPL-2/ERK MAPK pathway. Immunol. Rev. 246, 168–182 (2012).

    PubMed  Google Scholar 

  26. Beinke, S. et al. NF-κB p105 negatively regulates TPL-2 MEK kinase activity. Mol. Cell. Biol. 23, 4739–4752 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Waterfield, M. R., Zhang, M., Norman, L. P. & Sun, S.-C. NF-κB1/p105 regulates lipopolysaccharide-stimulated MAP kinase signaling by governing the stability and function of the TPL-2 kinase. Mol. Cell 11, 685–694 (2003).

    CAS  PubMed  Google Scholar 

  28. Beinke, S., Robinson, M. J., Hugunin, M. & Ley, S. C. Lipopolysaccharide activation of the TPL-2/MEK/extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IκB kinase-induced proteolysis of NF-κB1 p105. Mol. Cell. Biol. 24, 9658–9667 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Robinson, M. J., Beinke, S., Kouroumalis, A., Tsichlis, P. N. & Ley, S. C. Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. Mol. Cell. Biol. 27, 7355–7364 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Roget, K. et al. IKK2 regulates TPL-2 activation of ERK-1/2 MAP kinases by direct phosphorylation of TPL-2 serine 400. Mol. Cell. Biol. 32, 4684–4690 (2012). References 26–30 establish the direct regulation of TPL2 activation by IKK2-mediated phosphorylation of p105, showing a direct link between ERK1 and ERK2 activation and NF-κB activation in TLR-stimulated macrophages.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Rincon, M. & Davis, R. J. Regulation of the immune response by stress-activated protein kinases. Immunol. Rev. 228, 212–224 (2009).

    CAS  PubMed  Google Scholar 

  32. Han, M. S. et al. JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218–222 (2013). This is the first study to provide clear genetic evidence of a role for JNK in regulating gene expression in TLR-stimulated macrophages.

    CAS  PubMed  Google Scholar 

  33. Martinez, F. O., Helming, L. & Gordon, S. Alternative activation of macrophages: an immunologic functional perspective. Annu. Rev. Immunol. 27, 451–483 (2009).

    CAS  PubMed  Google Scholar 

  34. Odegaard, J. I. & Chawla, A. Alternative macrophage activation and metabolism. Annu. Rev. Pathol. 6, 275–297 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Dumitru, C. D. et al. TNFα induction by LPS is regulated post-transcriptionally via a TPL2/ERK-dependent pathway. Cell 103, 1071–1083 (2000).

    CAS  PubMed  Google Scholar 

  36. Kaiser, F. et al. TPL-2 negatively regulates interferon-β production in macrophages and myeloid dendritic cells. J. Exp. Med. 206, 1863–1871 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Mielke, L. A. et al. Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 production. J. Immunol. 183, 7984–7993 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang, H. T. et al. Coordinate regulation of TPL-2 and NF-κB signaling in macrophages by NF-κB1 p105. Mol. Cell. Biol. 32, 3438–3451 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Cohen, P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr. Opin. Cell Biol. 21, 1–8 (2009).

    Google Scholar 

  40. Beardmore, V. A. et al. Generation and characterization of p38β (MAPK11) gene-targeted mice. Mol. Cell. Biol. 25, 10454–10464 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kang, Y. J. et al. Macrophage deletion of p38α partially impairs lipopolysaccharide-induced cellular activation. J. Immunol. 180, 5075–5082 (2008).

    CAS  PubMed  Google Scholar 

  42. O'Keefe, S. J. et al. Chemical genetics define the roles of p38 and p38β in acute and chronic inflammation. J. Biol. Chem. 282, 34663–34671 (2007). This elegant study uses chemical genetics to establish that the anti-inflammatory effects of p38 inhibitors are mediated via p38α.

    CAS  PubMed  Google Scholar 

  43. Kim, C. et al. The kinase p38α serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nature Immunol. 9, 1019–1027 (2008).

    CAS  Google Scholar 

  44. Guma, M. et al. Pro- and anti-inflammatory functions of the p38 pathway in rheumatoid arthritis: Advantages of targeting upstream kinases MKK3 or MKK6. Arthritis Rheum. 64, 2887–2895 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Bohm, C. et al. The α-isoform of p38 MAPK specifically regulates arthritic bone loss. J. Immunol. 183, 5938–5947 (2009).

    PubMed  Google Scholar 

  46. Ananieva, O. et al. The kinases MSK1 and MSK2 act as negative regulators of Toll-like receptor signaling. Nature Immunol. 9, 1028–1036 (2008). Reference 44 and 46 provide genetic evidence for both pro- and anti-inflammatory roles for p38α, and the roles of MSK1 and MSK2 downstream of p38α, in regulating IL-10 production.

    CAS  Google Scholar 

  47. Cheung, P. C., Campbell, D. G., Nebreda, A. R. & Cohen, P. Feedback control of the protein kinase TAK1 by SAPK2a/p38α. EMBO J. 22, 5793–5805 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Gonzalez-Teran, B. et al. Eukaryotic elongation factor 2 controls TNF-α translation in LPS-induced hepatitis. J. Clin. Invest. 123, 164–178 (2013).

    CAS  PubMed  Google Scholar 

  49. Risco, A. et al. p38γ and p38δ kinases regulate the Toll-like receptor 4 (TLR4)-induced cytokine production by controlling ERK1/2 protein kinase pathway activation. Proc. Natl Acad. Sci. USA 109, 11200–11205 (2012). This study describes the surprising requirement for p38γ and p38δ for the maintenance of TPL2 protein levels in myeloid cells.

    CAS  PubMed  Google Scholar 

  50. Kotlyarov, A. et al. MAPKAP kinase 2 is essential for LPS-induced TNF-α biosynthesis. Nature Cell Biol. 1, 94–97 (1999).

    CAS  PubMed  Google Scholar 

  51. Hitti, E. et al. Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element. Mol. Cell. Biol. 26, 2399–2407 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Tiedje, C. et al. The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. PLoS Genet. 8, e1002977 (2012). This study establishes how p38α regulates Tnf translation via MK2 phosphorylation of tristetraprolin.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Kontoyiannis, D., Pasparakis, M., Pizarro, T. T., Cominelli, F. & Kollias, G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10, 387–398 (1999).

    CAS  PubMed  Google Scholar 

  54. Carballo, E., Gilkeson, G. S. & Blackshear, P. J. Bone marrow transplantation reproduces the tristetraprolin-deficiency syndrome in recombination activating gene-2 (−/−) mice. Evidence that monocyte/macrophage progenitors may be responsible for TNFα overproduction. J. Clin. Invest. 100, 986–995 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Qiu, L. Q., Stumpo, D. J. & Blackshear, P. J. Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. J. Immunol. 188, 5150–5159 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Ronkina, N. et al. The mitogen-activated protein kinase (MAPK)-activated protein kinases MK2 and MK3 cooperate in stimulation of tumor necrosis factor biosynthesis and stabilization of p38 MAPK. Mol. Cell. Biol. 27, 170–181 (2007).

    CAS  PubMed  Google Scholar 

  57. Ronkina, N. et al. Stress induced gene expression: a direct role for MAPKAP kinases in transcriptional activation of immediate early genes. Nucleic Acids Res. 39, 2503–2518 (2010).

    PubMed  PubMed Central  Google Scholar 

  58. Zaru, R., Ronkina, N., Gaestel, M., Arthur, J. S. & Watts, C. The MAPK-activated kinase Rsk controls an acute Toll-like receptor signaling response in dendritic cells and is activated through two distinct pathways. Nature Immunol. 8, 1227–1235 (2007).

    CAS  Google Scholar 

  59. Darragh, J., Ananieva, O., Courtney, A., Elcombe, S. & Arthur, J. S. MSK1 regulates the transcription of IL-1ra in response to TLR activation in macrophages. Biochem. J. 425, 595–602 (2010).

    CAS  PubMed  Google Scholar 

  60. Mackenzie, K. F. et al. MSK1 and 2 inhibit LPS induced prostaglandin production via an IL-10 feedback loop. Mol. Cell. Biol. 33, 1456–1467 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Brook, M. et al. Posttranslational regulation of tristetraprolin subcellular localization and protein stability by p38 mitogen-activated protein kinase and extracellular signal-regulated kinase pathways. Mol. Cell. Biol. 26, 2408–2418 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. MacKenzie, K. F. et al. PGE2 induces macrophage IL-10 production and a regulatory-like phenotype via a protein kinase A-SIK-CRTC3 pathway. J. Immunol. 190, 565–577 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Alvarez, Y., Municio, C., Alonso, S., Sanchez Crespo, M. & Fernandez, N. The induction of IL-10 by zymosan in dendritic cells depends on CREB activation by the coactivators CREB-binding protein and TORC2 and autocrine PGE2. J. Immunol. 183, 1471–1479 (2009).

    CAS  PubMed  Google Scholar 

  64. Caunt, C. J. & Keyse, S. M. Dual-specificity MAP kinase phosphatases (MKPs): shaping the outcome of MAP kinase signalling. FEBS J. 280, 489–504 (2012).

    PubMed  Google Scholar 

  65. Liu, Y., Shepherd, E. G. & Nelin, L. D. MAPK phosphatases--regulating the immune response. Nature Rev. Immunol. 7, 202–212 (2007).

    CAS  Google Scholar 

  66. Rodriguez, N. et al. Increased inflammation and impaired resistance to Chlamydophila pneumoniae infection in Dusp1−/− mice: critical role of IL-6. J. Leukoc. Biol. 88, 579–587 (2010).

    CAS  PubMed  Google Scholar 

  67. Hammer, M. et al. Increased inflammation and lethality of Dusp1−/− mice in polymicrobial peritonitis models. Immunology 131, 395–404 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Frazier, W. J. et al. Increased inflammation, impaired bacterial clearance, and metabolic disruption after gram-negative sepsis in Mkp-1-deficient mice. J. Immunol. 183, 7411–7419 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Wang, X. et al. Knockout of Mkp-1 enhances the host inflammatory responses to Gram-positive bacteria. J. Immunol. 178, 5312–5320 (2007).

    CAS  PubMed  Google Scholar 

  70. Hammer, M. et al. Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10. Eur. J. Immunol. 35, 2991–3001 (2005).

    CAS  PubMed  Google Scholar 

  71. Valledor, A. F. et al. IFN-γ-mediated inhibition of MAPK phosphatase expression results in prolonged MAPK activity in response to M-CSF and inhibition of proliferation. Blood 112, 3274–3282 (2008).

    CAS  PubMed  Google Scholar 

  72. Lee, C. H. et al. Glutamine suppresses airway neutrophilia by blocking cytosolic phospholipase A2 via an induction of MAPK phosphatase-1. J. Immunol. 189, 5139–5146 (2012).

    CAS  PubMed  Google Scholar 

  73. Ayush, O. et al. Glutamine suppresses DNFB-induced contact dermatitis by deactivating p38 mitogen-activated protein kinase via induction of MAPK phosphatase-1. J. Invest. Dermatol. 133, 723–731 (2013).

    CAS  PubMed  Google Scholar 

  74. Ko, H. M. et al. Glutamine protects mice from lethal endotoxic shock via a rapid induction of MAPK phosphatase-1. J. Immunol. 182, 7957–7962 (2009).

    CAS  PubMed  Google Scholar 

  75. Abraham, S. M. et al. Antiinflammatory effects of dexamethasone are partly dependent on induction of dual specificity phosphatase 1. J. Exp. Med. 203, 1883–1889 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Maier, J. V. et al. Dual specificity phosphatase 1 knockout mice show enhanced susceptibility to anaphylaxis but are sensitive to glucocorticoids. Mol. Endocrinol. 21, 2663–2671 (2007).

    CAS  PubMed  Google Scholar 

  77. Wang, X. et al. The role of MAP kinase phosphatase-1 in the protective mechanism of dexamethasone against endotoxemia. Life Sci. 83, 671–680 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Cao, W., Bao, C., Padalko, E. & Lowenstein, C. J. Acetylation of mitogen-activated protein kinase phosphatase-1 inhibits Toll-like receptor signaling. J. Exp. Med. 205, 1491–1503 (2008). This is the first work to establish that DUSPs can be regulated by acetylation.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Jeffrey, K. L. et al. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nature Immunol. 7, 274–283 (2006).

    CAS  Google Scholar 

  80. Cornell, T. T., Rodenhouse, P., Cai, Q., Sun, L. & Shanley, T. P. Mitogen-activated protein kinase phosphatase 2 regulates the inflammatory response in sepsis. Infect. Immun. 78, 2868–2876 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Al-Mutairi, M. S. et al. MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. PLoS Pathog. 6, e1001192 (2010).

    PubMed  PubMed Central  Google Scholar 

  82. Grasset, M. F., Gobert-Gosse, S., Mouchiroud, G. & Bourette, R. P. Macrophage differentiation of myeloid progenitor cells in response to M-CSF is regulated by the dual-specificity phosphatase DUSP5. J. Leukoc. Biol. 87, 127–135 (2010).

    CAS  PubMed  Google Scholar 

  83. Zhang, Y. et al. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430, 793–797 (2004).

    CAS  PubMed  Google Scholar 

  84. Qian, F. et al. A non-redundant role for MKP5 in limiting ROS production and preventing LPS-induced vascular injury. EMBO J. 28, 2896–2907 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Guo, T. et al. The role of male chromosomal polymorphism played in spermatogenesis and the outcome of IVF/ICSI-ET treatment. Int. J. Androl. 35, 802–809 (2012).

    CAS  PubMed  Google Scholar 

  86. Roy, C. R. & Mocarski, E. S. Pathogen subversion of cell-intrinsic innate immunity. Nature Immunol. 8, 1179–1187 (2007).

    CAS  Google Scholar 

  87. Turk, B. E. Manipulation of host signalling pathways by anthrax toxins. Biochem. J. 402, 405–417 (2007).

    CAS  PubMed  Google Scholar 

  88. Ali, S. R. et al. Anthrax toxin induces macrophage death by p38 MAPK inhibition but leads to inflammasome activation via ATP leakage. Immunity 35, 34–44 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Halle, M. et al. The Leishmania surface protease GP63 cleaves multiple intracellular proteins and actively participates in p38 mitogen-activated protein kinase inactivation. J. Biol. Chem. 284, 6893–6908 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Ma, L. et al. An evolutionary analysis of trypanosomatid GP63 proteases. Parasitol. Res. 109, 1075–1084 (2011).

    PubMed  Google Scholar 

  91. Schorey, J. S. & Cooper, A. M. Macrophage signalling upon mycobacterial infection: the MAP kinases lead the way. Cell. Microbiol. 5, 133–142 (2003).

    CAS  PubMed  Google Scholar 

  92. Kim, K. H. et al. Mycobacterium tuberculosis Eis protein initiates suppression of host immune responses by acetylation of DUSP16/MKP-7. Proc. Natl Acad. Sci. USA 109, 7729–7734 (2010).

    Google Scholar 

  93. Trosky, J. E., Liverman, A. D. & Orth, K. Yersinia outer proteins: yops. Cell. Microbiol. 10, 557–565 (2008).

    CAS  PubMed  Google Scholar 

  94. Mukherjee, S. et al. Yersinia YopJ acetylates and inhibits kinase activation by blocking phosphorylation. Science 312, 1211–1214 (2006).

    CAS  PubMed  Google Scholar 

  95. Mittal, R., Peak-Chew, S. Y. & McMahon, H. T. Acetylation of MEK2 and IκB kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc. Natl Acad. Sci. USA 103, 18574–18579 (2006).

    CAS  PubMed  Google Scholar 

  96. Paquette, N. et al. Serine/threonine acetylation of TGFβ-activated kinase (TAK1) by Yersinia pestis YopJ inhibits innate immune signaling. Proc. Natl Acad. Sci. USA 109, 12710–12715 (2012). References 94–96 describe how Yersinia YopJ inhibits MAPK activation by the acetylation of MKKs.

    CAS  PubMed  Google Scholar 

  97. Trosky, J. E. et al. VopA inhibits ATP binding by acetylating the catalytic loop of MAPK kinases. J. Biol. Chem. 282, 34299–34305 (2007).

    CAS  PubMed  Google Scholar 

  98. Jones, R. M. et al. Salmonella AvrA coordinates suppression of host immune and apoptotic defenses via JNK pathway blockade. Cell Host Microbe 3, 233–244 (2008).

    CAS  PubMed  Google Scholar 

  99. Mazurkiewicz, P. et al. SpvC is a Salmonella effector with phosphothreonine lyase activity on host mitogen-activated protein kinases. Mol. Microbiol. 67, 1371–1383 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Li, H. et al. The phosphothreonine lyase activity of a bacterial type III effector family. Science 315, 1000–1003 (2007).

    CAS  PubMed  Google Scholar 

  101. Zhu, Y. et al. Structural insights into the enzymatic mechanism of the pathogenic MAPK phosphothreonine lyase. Mol. Cell 28, 899–913 (2007). References 99–101 establish that S. enterica - and Shigella spp.-encoded phosphothreonine lyases irreversibly inactivate MAPKs to modulate host immune responses.

    CAS  PubMed  Google Scholar 

  102. Brennan, D. F. & Barford, D. Eliminylation: a post-translational modification catalyzed by phosphothreonine lyases. Trends Biochem. Sci. 34, 108–114 (2009).

    CAS  PubMed  Google Scholar 

  103. Reiterer, V. et al. Shigella flexneri type III secreted effector OspF reveals new crosstalks of proinflammatory signaling pathways during bacterial infection. Cell. Signal. 23, 1188–1196 (2011).

    CAS  PubMed  Google Scholar 

  104. Odendall, C. et al. The Salmonella kinase SteC targets the MAP kinase MEK to regulate the host actin cytoskeleton. Cell Host Microbe 12, 657–668 (2012). This study describes how SteC kinase modulates S. enterica virulence by activating ERK1 and ERK2 via direct phosphorylation of MKK1 and MKK2.

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Figueira, R. & Holden, D. W. Functions of the Salmonella pathogenicity island 2 (SPI-2) type III secretion system effectors. Microbiology 158, 1147–1161 (2012).

    CAS  PubMed  Google Scholar 

  106. Dar, A. C. & Shokat, K. M. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu. Rev. Biochem. 80, 769–795 (2011).

    CAS  PubMed  Google Scholar 

  107. Goldstein, D. M., Kuglstatter, A., Lou, Y. & Soth, M. J. Selective p38α inhibitors clinically evaluated for the treatment of chronic inflammatory disorders. J. Med. Chem. 53, 2345–2353 (2010).

    CAS  PubMed  Google Scholar 

  108. Genovese, M. C. et al. A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis. J. Rheumatol. 38, 846–854 (2011).

    CAS  PubMed  Google Scholar 

  109. Cohen, S. B. et al. Evaluation of the efficacy and safety of pamapimod, a p38 MAP kinase inhibitor, in a double-blind, methotrexate-controlled study of patients with active rheumatoid arthritis. Arthritis Rheum. 60, 335–344 (2009).

    CAS  PubMed  Google Scholar 

  110. Damjanov, N., Kauffman, R. S. & Spencer-Green, G. T. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies. Arthritis Rheum. 60, 1232–1241 (2009).

    PubMed  Google Scholar 

  111. Lomas, D. A. et al. An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease. J. Clin. Pharmacol. 52, 416–424 (2012).

    CAS  PubMed  Google Scholar 

  112. Anand, P. et al. Clinical trial of the p38 MAP kinase inhibitor dilmapimod in neuropathic pain following nerve injury. Eur. J. Pain 15, 1040–1048 (2011).

    CAS  PubMed  Google Scholar 

  113. Ninomiya-Tsuji, J. et al. A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase. J. Biol. Chem. 278, 18485–18490 (2003).

    CAS  PubMed  Google Scholar 

  114. Pauls, E. et al. Essential role for IKKβ in production of type 1 interferons by plasmacytoid dendritic cells. J. Biol. Chem. 287, 19216–19228 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Hegen, M., Gaestel, M., N. Ickerson-Nutter, C. L., Lin, L. L. & Telliez, J. B. MAPKAP kinase 2-deficient mice are resistant to collagen-induced arthritis. J. Immunol. 177, 1913–1917 (2006).

    CAS  PubMed  Google Scholar 

  116. Mourey, R. J. et al. A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor-α production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation. J. Pharmacol. Exp. Ther. 333, 797–807 (2010).

    CAS  PubMed  Google Scholar 

  117. Thiel, M. J. et al. Central role of the MEK/ERK MAP kinase pathway in a mouse model of rheumatoid arthritis: potential proinflammatory mechanisms. Arthritis Rheum. 56, 3347–3357 (2007).

    CAS  PubMed  Google Scholar 

  118. George, D. & Salmeron, A. Cot/Tpl-2 protein kinase as a target for the treatment of inflammatory disease. Curr. Top. Med. Chem. 9, 611–622 (2009).

    CAS  PubMed  Google Scholar 

  119. Kontoyiannis, D. et al. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J. Exp. Med. 196, 1563–1574 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Zhang, T. et al. Discovery of potent and selective covalent inhibitors of JNK. Chem. Biol. 19, 140–154 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Wilhelmsen, K., Mesa, K. R., Lucero, J., Xu, F. & Hellman, J. ERK5 protein promotes, whereas MEK1 protein differentially regulates, the Toll-like receptor 2 protein-dependent activation of human endothelial cells and monocytes. J. Biol. Chem. 287, 26478–26494 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  122. Carlson, S. M. et al. Large-scale discovery of ERK2 substrates identifies ERK-mediated transcriptional regulation of ETV3. Sci. Signal. 4, rs11 (2011).

    PubMed  PubMed Central  Google Scholar 

  123. Cargnello, M. & Roux, P. P. Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases. Microbiol. Mol. Biol. Rev. 75, 50–83 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. O'Connell, R. M., Taganov, K. D., Boldin, M. P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl Acad. Sci. USA 104, 1604–1609 (2007).

    CAS  PubMed  Google Scholar 

  125. Fleming, Y. et al. Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. Biochem. J. 352, 145–154 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Tournier, C. et al. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 15, 1419–1426 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Zou, H. et al. Differential requirement of MKK4 and MKK7 in JNK activation by distinct scaffold proteins. FEBS Lett. 581, 196–202 (2007).

    CAS  PubMed  Google Scholar 

  128. Bardwell, L. Mechanisms of MAPK signalling specificity. Biochem. Soc. Trans. 34, 837–841 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Symons, A., Beinke, S. & Ley, S. C. MAP kinase kinase kinases and innate immunity. Trends Immunol. 27, 40–48 (2006).

    CAS  PubMed  Google Scholar 

  130. Dhanasekaran, D. N., Kashef, K., Lee, C. M., Xu, H. & Reddy, E. P. Scaffold proteins of MAP-kinase modules. Oncogene 26, 3185–3202 (2007).

    CAS  PubMed  Google Scholar 

  131. Paul, A. et al. Involvement of mitogen-activated protein kinase homologues in the regulation of lipopolysaccharide-mediated induction of cyclo-oxygenase-2 but not nitric oxide synthase in RAW 264.7 macrophages. Cell. Signal. 11, 491–497 (1999).

    CAS  PubMed  Google Scholar 

  132. Caivano, M. Role of MAP kinase cascades in inducing arginine transporters and nitric oxide synthetase in RAW264 macrophages. FEBS Lett. 429, 249–253 (1998).

    CAS  PubMed  Google Scholar 

  133. Chan, E. D. et al. Induction of inducible nitric oxide synthase-NO by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK, and NF-κB signaling pathways. Infect. Immun. 69, 2001–2010 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Chen, C., Chen, Y. H. & Lin, W. W. Involvement of p38 mitogen-activated protein kinase in lipopolysaccharide-induced iNOS and COX-2 expression in J774 macrophages. Immunology 97, 124–129 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Bedard, K. & Krause, K. H. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87, 245–313 (2007).

    CAS  PubMed  Google Scholar 

  136. El-Benna, J., Dang, P. M., Gougerot-Pocidalo, M. A., Marie, J. C. & Braut-Boucher, F. p47phox, the phagocyte NADPH oxidase/NOX2 organizer: structure, phosphorylation and implication in diseases. Exp. Mol. Med. 41, 217–225 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Laroux, F. S., Romero, X., Wetzler, L., Engel, P. & Terhorst, C. Cutting edge: MyD88 controls phagocyte NADPH oxidase function and killing of Gram-negative bacteria. J. Immunol. 175, 5596–5600 (2005).

    CAS  PubMed  Google Scholar 

  138. Dang, P. M. et al. A specific p47phox -serine phosphorylated by convergent MAPKs mediates neutrophil NADPH oxidase priming at inflammatory sites. J. Clin. Invest. 116, 2033–2043 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Parsa, K. V., Butchar, J. P., Rajaram, M. V., Cremer, T. J. & Tridandapani, S. The tyrosine kinase Syk promotes phagocytosis of Francisella through the activation of Erk. Mol. Immunol. 45, 3012–3021 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Blander, J. M. & Medzhitov, R. Regulation of phagosome maturation by signals from Toll-like receptors. Science 304, 1014–1018 (2004).

    CAS  PubMed  Google Scholar 

  141. Rahighi, S. et al. Specific recognition of linear ubiquitin chains by NEMO is important for NF-κB activation. Cell 136, 1098–1109 (2009).

    CAS  PubMed  Google Scholar 

  142. Emmerich, C.H., Schmukle, A.C. & Walczak, H. The emerging role of linear ubiquitination in cell signaling. Sci. Signal. 4, re5 (2011).

    PubMed  Google Scholar 

  143. Zak, D.E. et al. Systems analysis identifies an essential role for SHANK-associated RH domain-interacting protein (SHARPIN) in macrophage Toll-like receptor 2 (TLR2) responses. Proc. Natl Acad. Sci. USA 108, 11536–11541 (2011).

    CAS  PubMed  Google Scholar 

  144. Brondello, J. M., Pouyssegur, J. & McKenzie, F. R. Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286, 2514–2517 (1999).

    CAS  PubMed  Google Scholar 

  145. Lin, Y. W. & Yang, J. L. Cooperation of ERK and SCFSkp2 for MKP-1 destruction provides a positive feedback regulation of proliferating signaling. J. Biol. Chem. 281, 915–926 (2006).

    CAS  PubMed  Google Scholar 

  146. Zhou, B. et al. Targeting mycobacterium protein tyrosine phosphatase B for antituberculosis agents. Proc. Natl Acad. Sci. USA 107, 4573–4578 (2010).

    CAS  PubMed  Google Scholar 

  147. Guo, X. et al. Regulation of the severity of neuroinflammation and demyelination by TLR-ASK1-p38 pathway. EMBO Mol. Med. 2, 504–515 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Sebolt-Leopold, J. S. Advances in the development of cancer therapeutics directed against the RAS-mitogen-activated protein kinase pathway. Clin. Cancer Res. 14, 3651–3656 (2008).

    CAS  PubMed  Google Scholar 

  149. Flaherty, K. T. et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 367, 107–114 (2012).

    CAS  PubMed  Google Scholar 

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Acknowledgements

J.S.C.A. and S.C.L. are supported by the UK Medical Research Council. The authors would like to thank P. Cohen (University of Dundee, UK), R. Davis (University of Massachusetts, Massachusetts, USA), D. Holden (Imperial College London, UK) and S. Smale (University of California, Los Angeles, California, USA) for their criticisms and advice in the writing of this Review.

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Glossary

Inflammasome

A molecular complex of several proteins that cleaves pro-interleukin-1β (pro-IL-1β) and pro-IL-18 following assembly, thereby producing active IL-1β and IL-18.

E3 ubiquitin ligase

An enzyme that is required to attach the molecular tag ubiquitin to proteins. Depending on the position and the number of the ubiquitin molecules that are attached, the ubiquitin tag can target proteins for degradation in the proteasomal complex, sort them to specific subcellular compartments or modify their biological activity.

Scaffold proteins

Proteins that can bind to multiple proteins in a specific signalling cascade. As a result they can mediate the formation of multiprotein complexes that constitute a signalling pathway. This can help to coordinate the regulation of signalling or to promote the localization of a complex to a specific subcellular location.

K/BxN transgenic mice

A mouse strain formed by crossing non-obese diabetic (NOD)/Lt mice with C57BL/6 KRN T cell receptor-transgenic mice in which T cells recognize a peptide from the self antigen glucose-6-phosphate isomerase (GPI). These mice develop arthritis that is mediated, and transferable, by circulating antibodies against GPI.

Small interfering RNA

(siRNA). Short double-stranded RNAs of 19–23 nucleotides that induce RNA interference, which is a post-transcriptional process that leads to gene silencing in a sequence-specific manner.

Insulin resistance

A condition in which cells in the body fail to respond to changes in insulin levels. As insulin stimulates glucose uptake by muscle and adipose cells while inhibiting glucose production by the liver, this results in elevated levels of blood glucose. Insulin resistance can be an indication of the development of type 2 diabetes.

M1 macrophage

A pro-inflammatory macrophage phenotype that is induced by Toll-like receptor ligands (such as lipopolysaccharide) and interferon-γ. M1 macrophages express, among other things, inducible nitric oxide synthase and nitric oxide.

Glucocorticoids

A group of compounds that belongs to the corticosteroid family. These compounds can either be naturally produced (hormones) or can be synthetic. They affect metabolism and have anti-inflammatory and immunosuppressive effects. Many synthetic glucocorticoids (for example, dexamethasone) are used in clinical medicine as anti-inflammatory drugs.

p300

p300, along with CREB-binding protein (CBP), are co-activator proteins that interact with interferon-regulatory factors and other transcription factors, which promote the recruitment of the RNA polymerase holoenzyme and that allow the transcriptional activation of the interferon (IFN) genes. In addition, p300 and CBP have a histone acetyltransferase activity, which endows these proteins with the capacity to influence chromatin activity by modulating nucleosomal histones.

Caecal puncture and ligation

An experimental model of peritonitis in rodents, in which the caecum is ligated and then punctured to form a small hole. This leads to leakage of intestinal bacteria into the peritoneal cavity and subsequent peritoneal infection.

Local Shwartzman reaction

This is a two-step inflammatory model in which a specific site, normally in the skin, is first sensitized by a local injection of an inflammatory agent such as bacterial endotoxin. A subsequent intravenous injection of the inflammatory agent is then used to invoke the reaction at the sensitized site. Typically this is characterized by haemorrahagic necrosis which develops within 24 hours of the second injection.

NADPH oxidase

An enzyme system that consists of multiple cytosolic and membrane-bound subunits. The complex is assembled in activated neutrophils mainly on the phagolysosomal membrane. NADPH oxidase uses electrons from NADPH to reduce molecular oxygen to form superoxide anions. Superoxide anions are enzymatically converted to hydrogen peroxide, which is converted by myeloperoxidase to hypochloric acid — a highly toxic and microbicidal agent.

Type III secretion systems

Specialized molecular machines present in some bacteria that allow the translocation of bacterial proteins into host cells.

β-elimination

A reaction that results in the loss of atoms or atom groups and in the formation of a new pi bond. The β-elimination of phosphate from phosphotheronine results in the formation of dehydrobutyrine, which contains a CH3–CH side chain with a pi bond that links the side chain to the peptide backbone.

MicroRNA

Single-stranded RNA molecules of approximately 21–23 nucleotides in length that are thought to regulate the expression of other genes.

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Arthur, J., Ley, S. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13, 679–692 (2013). https://doi.org/10.1038/nri3495

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