Altered Dendritic Cell Phenotype in Response to Leishmania amazonensis Amastigote Infection Is Mediated by MAP Kinase, ERK

Department of Veterinary Pathology, Iowa State University, Ames, Iowa 50011, USA.
American Journal Of Pathology (Impact Factor: 4.59). 05/2009; 174(5):1818-26. DOI: 10.2353/ajpath.2009.080905
Source: PubMed


Initiation of productive immune responses against Leishmania depends on the successful transition of dendritic cells (DC) from an immature to a mature phenotype. This process is characterized by high CD40 surface expression as well as interleukin-12 production, which are frequently seen in response to L. major infection. In vivo footpad infection of C3HeB/FeJ mice for 7 days with L. amazonensis promoted an immature CD11c(+) DC phenotype characterized by both significantly low CD40 surface expression and significantly decreased interleukin-12p40 production compared with L. major infection of these same mice. In vitro infection of bone marrow-derived dendritic cells with L. amazonensis amastigotes resulted in rapid and significant phosphorylation of the mitogen activated protein kinase, extracellular signal-regulated kinase 1/2, observed within minutes of exposure to the parasite. Infection with L. amazonensis promastigotes led to increased 1/2 phosphorylation after 4 hours of infection compared with L. major infection, which correlated with promastigote transformation into amastigotes. Treatment of bone marrow-derived dendritic cells with a mitogen activated protein kinase kinase-specific inhibitor, PD98059, led to regained surface CD40 expression and interleukin-12p40 production following L. amazonensis amastigote infection compared with non-treated, infected DC. Treatment of L. amazonensis-infected mice with the highly-specific mitogen activated protein kinase kinase inhibitor, CI-1040, enhanced surface CD40 expression on CD11c(+) DC obtained from the draining lymph node. L. amazonensis amastigotes, through activation of extracellular signal-regulated kinase 1/2, inhibit the ability of DC to undergo proper maturation both in vitro and in vivo.

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    • "The response is characterized by a poor initial inflammatory response and ineffective T cell-mediated immunity [2], [12]. These results correspond to specific effects on antigen presenting cell (APC) function during infection that could, in part, account for the poor adaptive immune response associated with this parasite [13], [14]. However, several studies have demonstrated that simply enhancing a Th1 response either through immune modulation or using animals deficient in IL-10 has, at most, only modest effects on the long-term disease outcomes [2], [15], [16], [17]. "
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    ABSTRACT: Footpad infection of C3HeB/FeJ mice with Leishmania amazonensis leads to chronic lesions accompanied by large parasite loads. Co-infecting these animals with L. major leads to induction of an effective Th1 immune response that can resolve these lesions. This cross-protection can be recapitulated in vitro by using immune cells from L. major-infected animals to effectively activate L. amazonensis-infected macrophages to kill the parasite. We have shown previously that the B cell population and their IgG2a antibodies are required for effective cross-protection. Here we demonstrate that, in contrast to L. major, killing L. amazonensis parasites is dependent upon FcRγ common-chain and NADPH oxidase-generated superoxide from infected macrophages. Superoxide production coincided with killing of L. amazonensis at five days post-activation, suggesting that opsonization of the parasites was not a likely mechanism of the antibody response. Therefore we tested the hypothesis that non-specific immune complexes could provide a mechanism of FcRγ common-chain/NADPH oxidase dependent parasite killing. Macrophage activation in response to soluble IgG2a immune complexes, IFN-γ and parasite antigen was effective in significantly reducing the percentage of macrophages infected with L. amazonensis. These results define a host protection mechanism effective during Leishmania infection and demonstrate for the first time a novel means by which IgG antibodies can enhance killing of an intracellular pathogen.
    PLoS ONE 09/2014; 9(9):e106426. DOI:10.1371/journal.pone.0106426 · 3.23 Impact Factor
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    • "Lin et al. have shown that the ERK signaling pathway is required for DC maturation and cytokine production by polysaccharide purified from Ganoderma lucidum [51]. In contrast, the ERK pathway has also been shown to lead to differentiation of tolerogenic DCs [52]. Moreover, a previous study has shown that ERK and JNK signaling pathways activation in DCs favors a Th2 response, whereas p38 pathway activation favors a Th1 response [53–55]. "
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    Evidence-based Complementary and Alternative Medicine 08/2013; 2013:761454. DOI:10.1155/2013/761454 · 1.88 Impact Factor
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    • "The suppression of host cell activation can be initiated at the stage of amastigote– host contact. On one hand, L. amazonensis amastigotes can infect human DCs through multiple receptor–ligand interactions such as antibodies/Fc receptors, complement components/component receptors, and proteoglycans/heparin-binding proteins (Bosetto and Giorgio, 2007), leading to altered DC activation and impaired responsiveness to exogenous stimuli through ERK/MAP kinasemediated mechanisms (Boggiatto et al., 2009). On the other hand, L. amazonensis amastigotes can expose phosphatidylserine (PS) on their surface, leading to enhanced parasite growth and host suppression through IL-10 and TGF-β production by host cells (Wanderley et al., 2006). "
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    ABSTRACT: Infection with Leishmania amazonensis and other members of the Leishmania mexicana complex can lead to diverse clinical manifestations, some of which are relatively difficult to control, even with standard chemotherapy. Diffuse cutaneous leishmaniasis (CL) is a rare but severe form, and its clinical hallmark is excessive parasitic growth in infected cells accompanied by profound impairments in host immune responses to the parasites. Since these parasites also cause non-healing CL in most inbred strains of mice, these animals are valuable models for dissecting the mechanisms of persistent infection and disease pathogenesis. In comparison to other Leishmania species, L. amazonensis infections are most remarkable for their ability to repress the activation and effector functions of macrophages, dendritic cells, and CD4(+) T cells, implying discrete mechanisms at work. In addition to this multilateral suppression of host innate and adaptive immunity, the activation of types I and II interferon-mediated responses and autophagic/lipid metabolic pathways actually promotes rather than restrains L. amazonensis infection. These seemingly contradictory findings reflect the remarkable adaptation of the parasites to the ancient defense machinery of the host, as well as the complex parasite-host interactions at different stages of infection, which collectively contribute to non-healing leishmaniasis in the New World. This review article highlights new evidence that reveals the strategies utilized by L. amazonensis parasites to subvert or modulate host innate defense machinery in neutrophils and macrophages, as well as the regulatory roles of host innate responses in promoting parasite survival and replication within the huge parasitophorous vacuoles. A better understanding of unique features in host responses to these parasites at early and late stages of infection is important for the rational design of control strategies for non-healing leishmaniasis.
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