Interleukin-4 responsive dendritic cells are dispensable to host resistance against Leishmania mexicana infection. Osero, B. O., Cele, Z., Aruleba, R. T., Maine, R. A, Ozturk, M., Lutz, M. B, Brombacher, F., & Hurdayal, R. Frontiers in Immunology, 12:759021, Frontiers, jan, 2022. Paper doi abstract bibtex IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4R$α$-/- global knockout miouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. Mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4R$α$ on CD11c+ DCs were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control, IL-4R$α$-/lox mice. Our results show that CL disease progression in BALB/c mice is independent of IL-4R$α$ signaling on DCs as CD11ccreIL-4R$α$-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-$γ$ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, IL-4 production in CD11ccreIL-4R$α$-/lox mice was significantly increased with an increasing trend of IL-13 compared to littermate controls. Moreover, the absence of IL-4R$α$ signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4R$α$-/lox mice due to greater total cell infiltration into the lymph node. The recruitment of macrophages, DCs, neutrophils, and MoDCs into LN was comparable to littermate IL-4R$α$-/lox mice. Interestingly, the similar levels of IL-12p70 and IL-10 produced by BMDCs between CD11ccreIL-4R$α$-/lox mice and littermate controls highlighted unimpaired IL-4-mediated DC instruction. Nevertheless, maturation/activation and nitrite/urea production were not affected. Together, this study suggests that IL-4 R$α$ signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.
@article{Osero2022,
abstract = {IL-4 and IL-13 cytokines have been associated with a non-healing phenotype in murine leishmaniasis in L. mexicana -infected BALB/c mice as demonstrated in IL-4−/−, IL-13−/− and IL-4R$\alpha$-/- global knockout miouse studies. However, it is unclear from the studies which cell-type-specific IL-4/IL-13 signaling mediates protection to L. mexicana. Previous studies have ruled out a role for IL-4-mediated protection on CD4+ T cells during L. mexicana infections. A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. Mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4R$\alpha$ on CD11c+ DCs were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control, IL-4R$\alpha$-/lox mice. Our results show that CL disease progression in BALB/c mice is independent of IL-4R$\alpha$ signaling on DCs as CD11ccreIL-4R$\alpha$-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-$\gamma$ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, IL-4 production in CD11ccreIL-4R$\alpha$-/lox mice was significantly increased with an increasing trend of IL-13 compared to littermate controls. Moreover, the absence of IL-4R$\alpha$ signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4R$\alpha$-/lox mice due to greater total cell infiltration into the lymph node. The recruitment of macrophages, DCs, neutrophils, and MoDCs into LN was comparable to littermate IL-4R$\alpha$-/lox mice. Interestingly, the similar levels of IL-12p70 and IL-10 produced by BMDCs between CD11ccreIL-4R$\alpha$-/lox mice and littermate controls highlighted unimpaired IL-4-mediated DC instruction. Nevertheless, maturation/activation and nitrite/urea production were not affected. Together, this study suggests that IL-4 R$\alpha$ signaling on DCs is not key in the regulation of immune-mediated protection in mice against L. mexicana infection.},
author = {Osero, Bernard Ong'ondo and Cele, Zama and Aruleba, Raphael Taiwo and Maine, Rebeng A and Ozturk, Mumin and Lutz, Manfred B and Brombacher, Frank and Hurdayal, Ramona},
doi = {10.3389/FIMMU.2021.759021},
file = {:C$\backslash$:/Users/01462563/AppData/Local/Mendeley Ltd./Mendeley Desktop/Downloaded/Osero et al. - 2022 - Interleukin-4 responsive dendritic cells are dispensable to host resistance against Leishmania mexicana infection.pdf:pdf},
issn = {1664-3224},
journal = {Frontiers in Immunology},
keywords = {Dendritic Cells,IL-4,IL-4R$\alpha$,Leishmania mexicana,Mice,OA,fund{\_}ack,original},
mendeley-tags = {OA,fund{\_}ack,original},
month = {jan},
pages = {759021},
pmid = {35154068},
publisher = {Frontiers},
title = {{Interleukin-4 responsive dendritic cells are dispensable to host resistance against Leishmania mexicana infection}},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2021.759021/full},
volume = {12},
year = {2022}
}
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A candidate for this role may be non-lymphocyte cells, particularly DCs, as was previously shown in L. major infections, where IL-4 production drives dendritic cell-IL-12 production thereby mediating a type 1 immune response. However, it is unclear if this IL-4-instruction of type 1 immunity also occurs in CL caused by L. Mexicana, since the outcome of cutaneous leishmaniasis often depends on the infecting Leishmania species. Thus, BALB/c mice with cell-specific deletion of the IL-4R$α$ on CD11c+ DCs were infected with L. mexicana promastigotes in the footpad and the clinical phenotype, humoral and cellular immune responses were investigated, compared to the littermate control, IL-4R$α$-/lox mice. Our results show that CL disease progression in BALB/c mice is independent of IL-4R$α$ signaling on DCs as CD11ccreIL-4R$α$-/lox mice had similar footpad lesion progression, parasite loads, humoral responses (IgE, IgG1, IgG 2a/b), and IFN-$γ$ cytokine secretion in comparison to littermate controls. Despite this comparable phenotype, IL-4 production in CD11ccreIL-4R$α$-/lox mice was significantly increased with an increasing trend of IL-13 compared to littermate controls. Moreover, the absence of IL-4R$α$ signaling did not significantly alter the frequency of CD4 and CD8 lymphocytes nor their activation, or memory phenotype compared to littermate controls. However, these populations were significantly increased in CD11ccreIL-4R$α$-/lox mice due to greater total cell infiltration into the lymph node. The recruitment of macrophages, DCs, neutrophils, and MoDCs into LN was comparable to littermate IL-4R$α$-/lox mice. Interestingly, the similar levels of IL-12p70 and IL-10 produced by BMDCs between CD11ccreIL-4R$α$-/lox mice and littermate controls highlighted unimpaired IL-4-mediated DC instruction. Nevertheless, maturation/activation and nitrite/urea production were not affected. 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