RESUMO
Leishmaniasis is a parasitic disease affecting â¼12 million people. Control of infection (e.g. in C57BL/6 mice) results from IL-12-dependent production of IFNγ by Th1/Tc1 cells. In contrast, BALB/c mice succumb to infection because of preferential Th2-type cytokine induction. Infected dendritic cells (DC) represent important sources of IL-12. Genetically determined differences in DC IL-1α/ß production contribute to disease outcome. Whereas the course of disease was not dramatically altered in IL-1RI(-/-) mice, local administration of IL-1α to infected C57BL/6 mice improved disease outcome. To definitively elucidate the involvement of IL-1 in immunity against leishmaniasis, we now utilized IL-1α/ß-double-deficient C57BL/6 mice. C57BL/6 mice are believed to be a good surrogate model for human, self limited cutaneous leishmaniasis (CL). Leishmania major-infected IL-1α/ß(-/-) mice were resistant to experimental CL comparable to controls. In addition, DC-based vaccination against leishmaniasis in C57BL/6 mice was independent of IL-1. Thus, in Leishmania-resistant C57BL/6 mice, IL-1 signalling is dispensable for protection.
Assuntos
Interleucina-1/imunologia , Leishmania major/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Modelos Animais de Doenças , Humanos , Interleucina-1alfa/administração & dosagem , Interleucina-1alfa/deficiência , Interleucina-1alfa/genética , Interleucina-1beta/deficiência , Interleucina-1beta/genética , Leishmaniose Cutânea/imunologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/prevenção & controle , Macrófagos/imunologia , Macrófagos/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais/imunologiaRESUMO
Resistance to leishmaniasis in C57BL/6 mice depends on Th1/Tc1 cells. BALB/c mice preferentially develop Th2 immunity and succumb to infection. We now assessed the role of IL-17 in cutaneous leishmaniasis. During the course of Leishmania major infection, BALB/c CD4 cells and neutrophils produced increased amounts of IL-17 as compared with cells from C57BL/6 mice. This increase was associated with significantly increased IL-23 release from L. major-infected BALB/c dendritic cells (DC), whereas IL-6 and TGF-beta1 production by BALB/c and C57BL/6 DC were comparable. Interestingly, lesion sizes in infected IL-17-deficient BALB/c mice were dramatically smaller and failed to progress as compared with those in control mice. Similar amounts of IL-4, IL-10, and IFN-gamma were produced by T cells from IL-17-deficient mice and control mice consistent with development of Th2-predominant immunity in all animals. Improved disease outcome was associated with decreased CXCL2-accumulation in lesion sites and decreased neutrophil immigration into lesions of infected IL-17-deficient mice confirming prior observations that enhanced neutrophil recruitment contributes to disease susceptibility in BALB/c mice. This study excludes an important facilitating role for IL-17 in Th1/Th2 development in L. major-infected BALB/c mice, and suggests that IL-23 production by L. major-infected DC maintains IL-17(+) cells that influence disease progression via regulation of neutrophil recruitment.
Assuntos
Predisposição Genética para Doença , Interleucina-17/fisiologia , Leishmaniose Cutânea/genética , Leishmaniose Cutânea/imunologia , Animais , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/parasitologia , Células Dendríticas/patologia , Progressão da Doença , Imunidade Celular/genética , Interleucina-17/biossíntese , Interleucina-17/deficiência , Interleucina-17/genética , Interleucina-23/metabolismo , Leishmania major/imunologia , Leishmaniose Cutânea/parasitologia , Leishmaniose Cutânea/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/imunologia , Neutrófilos/parasitologia , Neutrófilos/patologia , Especificidade da Espécie , Células Th2/imunologia , Células Th2/parasitologia , Células Th2/patologia , Regulação para Cima/genética , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Using a T helper (Th)1/Th2 disease model, we previously showed that genetically determined Th development depends on dendritic cell-derived interleukin (IL)-1alpha. In Leishmania major infections, Th1 immunity develops if IL-1alpha is present during T cell priming, whereas at later time points, IL-1alpha worsens disease outcome. In the present study, we determined the role of IL-1alpha in other Th2-mediated diseases. METHODS: BALB/c mice were subjected to delayed-type hypersensitivity (DTH) or ovalbumin (OVA)/alum-induced allergic asthma in the presence or absence of IL-1alpha. RESULTS: In DTH, mice treated with IL-1alpha during sensitization with keyhole limpet hemocyanin (KLH)/alum developed decreased footpad swelling associated with elevated KLH-specific interferon-gamma levels. In asthma, significantly decreased airway hypersensitivity responses (AHRs) were detected upon treatment with IL-1alpha during T cell priming. In contrast to control mice, IL-1alpha-treated mice showed reduced peribronchial inflammatory infiltrates. The bronchoalveolar lavage (BAL) fluid contained significantly decreased eosinophil numbers (approximately 50%), but 4 times more neutrophils. The BAL fluid of IL-1alpha-treated BALB/c exhibited reduced amounts of IL-5 and OVA-specific IgE serum levels. In contrast, IL-1alpha treatment at later time points after sensitization or during allergen challenge worsened AHR, had no effect on lung inflammation and BAL fluid cell composition. Furthermore, cytokine levels (IL-5, IL-13) and antigen-specific IgE were increased or unaltered under these conditions. CONCLUSION: Similarly to leishmaniasis, IL-1alpha administration during sensitization of Th2-mediated allergic reactions suppresses the course of disease by shifting the immune response towards Th1, whereas later treatments worsen disease outcome. Future studies will elucidate the therapeutic value of IL-1alpha in asthmatic patients.
Assuntos
Asma/imunologia , Hipersensibilidade Tardia/imunologia , Interleucina-1alfa/metabolismo , Compostos de Alúmen/administração & dosagem , Animais , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Contagem de Células , Eosinófilos/patologia , Feminino , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Imunoglobulina E/metabolismo , Interferon gama/metabolismo , Interleucina-1alfa/imunologia , Interleucina-5/análise , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/patologia , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Células Th2/imunologiaRESUMO
Migratory skin dendritic cells (DCs) are thought to play an important role in priming T cell immune responses against Leishmania major, but DC subtypes responsible for the induction of protective immunity against this pathogen are still controversial. In this study, we analyzed the role of Langerin(+) skin-derived DCs in the Leishmania model using inducible in vivo cell ablation. After physiologically relevant low-dose infection with L. major (1,000 parasites), mice depleted of all Langerin(+) DCs developed significantly smaller ear lesions with decreased parasite loads and a reduced number of CD4(+) Foxp3(+) regulatory T cells (T reg cells) as compared with controls. This was accompanied by increased interferon γ production in lymph nodes in the absence of Langerin(+) DCs. Moreover, selective depletion of Langerhans cells (LCs) demonstrated that the absence of LCs, and not Langerin(+) dermal DC, was responsible for the reduced T reg cell immigration and the enhanced Th1 response, resulting in attenuated disease. Our data reveal a unique and novel suppressive role for epidermal LCs in L. major infection by driving the expansion of T reg cells. A better understanding of the various roles of different DC subsets in cutaneous leishmaniasis will improve the development of a potent therapeutic/prophylactic vaccine.
Assuntos
Tolerância Imunológica , Células de Langerhans/imunologia , Leishmania major/imunologia , Leishmaniose Cutânea/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Animais , Modelos Animais de Doenças , Interferon gama/imunologia , Vacinas contra Leishmaniose/imunologia , Leishmaniose Cutânea/prevenção & controle , CamundongosRESUMO
Dendritic cell (DC)-derived IL-1α/ß plays a critical role in the induction of T helper type 1 (Th1)-dependent immunity against Leishmania. DCs from susceptible BALB/c mice produce less IL-1α/ß when compared with resistant C57BL/6 mice, contributing to aberrant Th2 development and ultimate death of infected mice. We have extended our studies of the role of IL-1 in leishmaniasis using IL-1RA(-/-) BALB/c mice that are characterized by upregulated IL-1 receptor signaling. Unexpectedly, infection of IL-1RA(-/-) mice led to significantly worsened disease outcome with larger lesions, dramatically higher parasite burdens, and decreased IFN-γ production by antigen-specific T cells. We determined that IL-1RA(-/-) DCs were more mature already in the steady state, exhibited less phagocytotic capacity, and IL-12 production in response to various stimuli was impaired. Our data suggest that in addition to effects on Th education, IL-1α/ß signaling also modulates DC homeostasis with increased signaling, leading to downmodulation of IL-12 synthesis and worsened disease outcome after infection with Leishmania major. Thus, the complex regulation of various members of the IL-1 cytokine family mediated through effects on both DCs and T cells critically contributes to disease outcome against this important human pathogen.