MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana

M.S. Al-Mutairi, L.C. Cadalbert, H.A. McGachy, M.S. Shweash, J. Schroeder, M. Kurnik, C.M. Sloss, C.E. Bryant, James Alexander, R.J. Plevin

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Abstract

In this study we generated a novel dual specific phosphatase 4 (DUSP4) deletion mouse using a targeted deletion strategy in order to examine the role of MAP kinase phosphatase-2 (MKP-2) in immune responses. Lipopolysaccharide (LPS) induced a rapid, time and concentration-dependent increase in MKP-2 protein expression in bone marrow-derived macrophages from MKP-2+/+ but not from MKP-2−/− mice. LPS-induced JNK and p38 MAP kinase phosphorylation was significantly increased and prolonged in MKP-2−/− macrophages whilst ERK phosphorylation was unaffected. MKP-2 deletion also potentiated LPS-stimulated induction of the inflammatory cytokines, IL-6, IL-12p40, TNF-α, and also COX-2 derived PGE2 production. However surprisingly, in MKP-2−/− macrophages, there was a marked reduction in LPS or IFNγ-induced iNOS and nitric oxide release and enhanced basal expression of arginase-1, suggesting that MKP-2 may have an additional regulatory function significant in pathogen-mediated immunity. Indeed, following infection with the intracellular parasite Leishmania mexicana, MKP-2−/− mice displayed increased lesion size and parasite burden, and a significantly modified Th1/Th2 bias compared with wild-type counterparts. However, there was no intrinsic defect in MKP-2−/− T cell function as measured by anti-CD3 induced IFN-γ production. Rather, MKP-2−/− bone marrow-derived macrophages were found to be inherently more susceptible to infection with Leishmania mexicana, an effect reversed following treatment with the arginase inhibitor nor-NOHA. These findings show for the first time a role for MKP-2 in vivo and demonstrate that MKP-2 may be essential in orchestrating protection against intracellular infection at the level of the macrophage.
Original languageEnglish
Article numbere1001192
JournalPLOS Pathogens
Volume6
Issue number11
DOIs
Publication statusPublished - Nov 2010

Keywords

  • MAP kinase phosphatase-2
  • leishmania
  • leishmania mexicana
  • innate immune-responses
  • N-terminal kinase
  • nitric-oxide synthase

Cite this

Al-Mutairi, M. S., Cadalbert, L. C., McGachy, H. A., Shweash, M. S., Schroeder, J., Kurnik, M., Sloss, C. M., Bryant, C. E., Alexander, J., & Plevin, R. J. (2010). MAP kinase phosphatase-2 plays a critical role in response to infection by Leishmania mexicana. PLOS Pathogens, 6(11), [e1001192]. https://doi.org/10.1371/journal.ppat.1001192