Abstract
We have recently demonstrated that MAP kinase phosphatase 2 (MKP-2) deficient C57BL/6 mice, unlike their wild-type counterparts, are unable to control infection with the protozoan parasite Leishmania mexicana. Increased susceptibility was associated with elevated Arginase-1 levels and reduced iNOS activity in macrophages as well as a diminished TH1 response. By contrast, in the present study footpad infection of MKP-2−/− mice with L. major resulted in a healing response as measured by lesion size and parasite numbers similar to infected MKP-2+/+ mice. Analysis of immune responses following infection demonstrated a reduced TH1 response in MKP-2−/− mice with lower parasite specific serum IgG2b levels, a lower frequency of IFN-γ and TNF-α producing CD4+ and CD8+ T cells and lower antigen stimulated spleen cell IFN-γ production than their wild-type counterparts. However, infected MKP-2−/− mice also had similarly reduced levels of antigen induced spleen and lymph node cell IL-4 production compared with MKP-2+/+ mice as well as reduced levels of parasite-specific IgG1 in the serum, indicating a general T cell hypo-responsiveness. Consequently the overall TH1/TH2 balance was unaltered in MKP-2−/− compared with wild-type mice. Although non-stimulated MKP-2−/− macrophages were more permissive to L. major growth than macrophages from MKP-2+/+ mice, reflecting their reduced iNOS and increased Arginase-1 expression, LPS/IFN-γ activation was equally effective at controlling parasite growth in MKP-2−/− and MKP-2+/+ macrophages. Consequently, in the absence of any switch in the TH1/TH2 balance in MKP-2−/− mice, no significant change in disease phenotype was observed.
Highlights
Leishmania species are protozoan parasites that are transmitted by infected female sandflies and cause a wide spectrum of diseases ranging from self-healing cutaneous lesions to fatal systemic disease
Given that MAP Kinase Phosphatase (MKP)-22/2 mice were previously found to be more susceptible to L. mexicana than their wild-type counterparts [21], no difference in lesion growth between MKP-22/2 and MAP kinase phosphatase 2 (MKP-2)+/+ mice was detected throughout the course of infection with L. major
While no specific direct defect in T cell function could be attributed to MKP-2 deficiency, a diminished parasite-specific TH1 and an enhanced TH2 response developed in MKP-22/2 mice infected with L. mexicana [21]
Summary
Leishmania species are protozoan parasites that are transmitted by infected female sandflies and cause a wide spectrum of diseases ranging from self-healing cutaneous lesions to fatal systemic disease. After entering their vertebrate host, promastigotes are taken up initially by neutrophils and macrophages and dendritic cells, where they turn rapidly into amastigotes and survive within parasitophorous vacuoles [1]. Activated T cells migrate to the site of infection where they release IFN-c and TNF-a which in turn upregulate inducible nitric oxide synthase (iNOS) in infected macrophages, enabling nitric oxide (NO) mediated killing of the intracellular parasites [6,7]. IL-4 in particular has been shown to promote alternative macrophage activation including increased expression of Arginase-1 [15], suppression of iNOS [16] and increased growth of L. major
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