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• W3043200126 abstract "Cutaneous leishmaniasis is a parasitic skin disease with ∼1 million new cases and about 30,000 annual deaths (Sacks and Noben-Trauth, 2002Sacks D. Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice.Nat Rev Immunol. 2002; 2: 845-858Crossref PubMed Scopus (897) Google Scholar). During blood feeding, sand flies inoculate parasites into host skin where they are ingested by phagocytes such as macrophages or neutrophils. Later, intracellular life forms of the parasites are ingested by dendritic cells, which then migrate to draining lymph nodes and release IL-12p40. This in turn activates IFNγ-producing CD8+ Tc1 and CD4+ T helper (Th) 1 T cells, enabling infected macrophages to kill intracellular parasites (Sacks and Noben-Trauth, 2002Sacks D. Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice.Nat Rev Immunol. 2002; 2: 845-858Crossref PubMed Scopus (897) Google Scholar). Inbred mouse strains have been studied as prototype models to understand Th1- versus Th2-type responses in Leishmania major infections. Resistant C57BL/6 mice develop self-healing lesions with long-lasting immunity against reinfection with the same Leishmania species associated with high levels of IFN-γ and IL-12p40. In contrast, BALB/c mice succumb to infection on the basis of their antigen-specific Th2/regulatory T-cell‒driven immune response with high IL-4 and IL-10 levels (Sacks and Noben-Trauth, 2002Sacks D. Noben-Trauth N. The immunology of susceptibility and resistance to Leishmania major in mice.Nat Rev Immunol. 2002; 2: 845-858Crossref PubMed Scopus (897) Google Scholar). Recently, it became clear that CD4+ Th17 cells and γδ T cells contribute to disease outcome by aggravating pathology through IL-17A–dependent neutrophil recruitment. Interestingly, the number of IL-17‒producing cells was dramatically higher in BALB/c mice than in C57BL/6 mice (Lopez Kostka et al., 2009Lopez Kostka S. Dinges S. Griewank K. Iwakura Y. Udey M.C. von Stebut E. IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.J Immunol. 2009; 182: 3039-3046Crossref PubMed Scopus (157) Google Scholar), and IL-17A−/− BALB/c mice as well as BALB/c mice depleted of neutrophils were protected from progressive disease (Lopez Kostka et al., 2009Lopez Kostka S. Dinges S. Griewank K. Iwakura Y. Udey M.C. von Stebut E. IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.J Immunol. 2009; 182: 3039-3046Crossref PubMed Scopus (157) Google Scholar; Tacchini-Cottier et al., 2000Tacchini-Cottier F. Zweifel C. Belkaid Y. Mukankundiye C. Vasei M. Launois P. et al.An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB/c mice infected with Leishmania major.J Immunol. 2000; 165: 2628-2636Crossref PubMed Scopus (229) Google Scholar). Previously, in lesions of L. major‒infected mice, mast cell (MC) activation and/or degranulation was observed (Wershil et al., 1994Wershil B.K. Theodos C.M. Galli S.J. Titus R.G. Mast cells augment lesion size and persistence during experimental Leishmania major infection in the mouse.J Immunol. 1994; 152: 4563-4571PubMed Google Scholar). In general, MCs play an important role in type I hypersensitivity and against intestinal worms (Dudeck et al., 2019Dudeck A. Köberle M. Goldmann O. Meyer N. Dudeck J. Lemmens S. et al.Mast cells as protectors of health.J Allergy Clin Immunol. 2019; 144: S4-S18Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar), and they can produce de novo‒generated and/or preformed Th1 and Th2 cytokines. MC-deficient KitW/W-v and KitW-sh/KitW-sh mice developed significantly increased lesion volumes and higher parasite burdens upon infection in line with decreased levels of Th1 cytokines compared with controls (Dudeck et al., 2011Dudeck A. Suender C.A. Kostka S.L. von Stebut E. Maurer M. Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function.Eur J Immunol. 2011; 41: 1883-1893Crossref PubMed Scopus (103) Google Scholar; Maurer et al., 2006Maurer M. Lopez Kostka S. Siebenhaar F. Moelle K. Metz M. Knop J. et al.Skin mast cells control T cell-dependent host defense in Leishmania major infections.FASEB J. 2006; 20: 2460-2467Crossref PubMed Scopus (105) Google Scholar). This effect was absent after local reconstitution with MC before infection. Interestingly, in the absence of MC, both the levels of Th1-associated IL-12 and/or IFN-γ as well as the levels of IL-17A were reduced (Dudeck et al., 2011Dudeck A. Suender C.A. Kostka S.L. von Stebut E. Maurer M. Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function.Eur J Immunol. 2011; 41: 1883-1893Crossref PubMed Scopus (103) Google Scholar). Because it was previously shown that under steady-state conditions, MC numbers in BALB/c mice are even higher (Cangussú et al., 2009Cangussú S.D. Souza C.C. Campos C.F. Vieira L.Q. Afonso L.C. Arantes R.M. Histopathology of Leishmania major infection: revisiting L. major histopathology in the ear dermis infection model.Mem Inst Oswaldo Cruz. 2009; 104: 918-922Crossref PubMed Scopus (21) Google Scholar; Villaseñor-Cardoso et al., 2008Villaseñor-Cardoso M.I. Salaiza N. Delgado J. Gutiérrez-Kobeh L. Pérez-Torres A. Becker I. Mast cells are activated by Leishmania mexicana LPG and regulate the disease outcome depending on the genetic background of the host.Parasite Immunol. 2008; 30: 425-434Crossref PubMed Scopus (22) Google Scholar), we analyzed the role of kit-dependent MC in susceptible BALB/c mice using congenic C.B6KitW-sh mice (Figure 1a) (Becker et al., 2011Becker M. Reuter S. Friedrich P. Doener F. Michel A. Bopp T. et al.Genetic variation determines mast cell functions in experimental asthma.J Immunol. 2011; 186: 7225-7231Crossref PubMed Scopus (39) Google Scholar). All mice were housed under specific pathogen-free conditions in the Translational Animal Research Center, Mainz, Germany and in accordance with institutional and federal guidelines. All experiments were undertaken with approved license from the Animal Care and Use Committee of the Region Rhineland-Palatinate, Germany. C.B6KitW-sh and control BALB/c mice were infected intradermally with physiologically relevant low-dose inocula (103) of parasites in both ears (Maurer et al., 2006Maurer M. Lopez Kostka S. Siebenhaar F. Moelle K. Metz M. Knop J. et al.Skin mast cells control T cell-dependent host defense in Leishmania major infections.FASEB J. 2006; 20: 2460-2467Crossref PubMed Scopus (105) Google Scholar). Interestingly, in stark contrast to KitW-sh/KitW-sh mice on the C57BL/6 background, C.B6KitW-sh mice developed significantly smaller lesion volumes and did not progress similar to wild types (Figure 2a). In line with this, local and systemic parasite burdens were significantly lower in the absence of MC than in wild-type mice 6 weeks after infection (Figure 2b).Figure 2Genetic deletion of MC improves disease outcome in susceptible BALB/c mice.Show full caption(a) MC-deficient and control BALB/c mice were infected with 1,000 metacyclic promastigotes in both ears. Lesion volumes were measured weekly and are reported as ellipsoids. C.B6KitW-sh mice were reconstituted locally with MC by the injection of 5 × 104 BMMC 4 weeks before infection. (b) Lesional and systemic parasite burdens were determined 6 weeks after infection in MC-deficient C.B6KitW-sh and BALB/c control mice. (c) After 6 weeks, LN cells were restimulated with SLA (25 μg/ml) for 48 h. Supernatants were assessed for IFNγ, IL-4, IL-10, IL-17A, and IL-12p40 levels by ELISA. (d) Differences in frequencies of infiltrating cells were analyzed in C.B6KitW-sh mice and BALB/c control mice by flow cytometry in infected ears 6 weeks after infection. (a, c) Data are presented as mean ± SEM, n = 3–5 independent experiments, ≥11 mice per group were used; ∗P ≤ 0.05, ∗∗P ≤ 0.005, ∗∗∗P ≤ 0.002. BMMC, bone marrow‒derived MC; h, hour; LN, lymph node; MC, mast cell; MHC II, major histocompatibility complex II; SLA, soluble Leishmania antigen.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (a) MC-deficient and control BALB/c mice were infected with 1,000 metacyclic promastigotes in both ears. Lesion volumes were measured weekly and are reported as ellipsoids. C.B6KitW-sh mice were reconstituted locally with MC by the injection of 5 × 104 BMMC 4 weeks before infection. (b) Lesional and systemic parasite burdens were determined 6 weeks after infection in MC-deficient C.B6KitW-sh and BALB/c control mice. (c) After 6 weeks, LN cells were restimulated with SLA (25 μg/ml) for 48 h. Supernatants were assessed for IFNγ, IL-4, IL-10, IL-17A, and IL-12p40 levels by ELISA. (d) Differences in frequencies of infiltrating cells were analyzed in C.B6KitW-sh mice and BALB/c control mice by flow cytometry in infected ears 6 weeks after infection. (a, c) Data are presented as mean ± SEM, n = 3–5 independent experiments, ≥11 mice per group were used; ∗P ≤ 0.05, ∗∗P ≤ 0.005, ∗∗∗P ≤ 0.002. BMMC, bone marrow‒derived MC; h, hour; LN, lymph node; MC, mast cell; MHC II, major histocompatibility complex II; SLA, soluble Leishmania antigen. Next, lymph nodes cells of the infected C.B6KitW-sh and control mice were restimulated with soluble Leishmania antigen (25 μg/ml) for 48 hours (Figure 2c). Interestingly, the levels of secreted IFN-γ, IL-4, and IL-10 were comparable in MC-deficient and wild-type BALB/c mice, demonstrating a Th2 phenotype with low levels of IFN-γ and high levels of IL-4 and IL-10. However, in contrast to BALB/c mice, C.B6KitW-sh mice exhibited significantly reduced levels of secreted IL-17A as well as IL-12p40, which correlated with reduced frequencies of immigrated neutrophils and dendritic cell in lesions (Figure 2d). In contrast, we did not observe differences in the lesional frequency of F4/80+ macrophages and/or CD4+ and CD8+ T cells. Our findings are thus in line with prior observations in C57BL/6 mice showing that MC-primed dendritic cells induced higher frequencies of IL-17A–producing Th17 cells (Dudeck et al., 2011Dudeck A. Suender C.A. Kostka S.L. von Stebut E. Maurer M. Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function.Eur J Immunol. 2011; 41: 1883-1893Crossref PubMed Scopus (103) Google Scholar). This has a strong effect on pathology in cutaneous leishmaniasis in BALB/c mice because IL-17 induction is highly relevant in leishmaniasis of susceptible BALB/c mice (Dietze-Schwonberg et al., 2018Dietze-Schwonberg K. Lorenz B. Kostka S.L. Schumak B. Gessner A. von Stebut E. Insufficient generation of Th17 cells in IL-23p19-deficient BALB/c mice protects against progressive cutaneous leishmaniasis.Exp Dermatol. 2018; 27: 101-103Crossref PubMed Scopus (4) Google Scholar; Lopez Kostka et al., 2009Lopez Kostka S. Dinges S. Griewank K. Iwakura Y. Udey M.C. von Stebut E. IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.J Immunol. 2009; 182: 3039-3046Crossref PubMed Scopus (157) Google Scholar), whereas in C57BL/6 mice, the absence of IL-17A does not affect disease outcome (Dietze-Schwonberg et al., 2019Dietze-Schwonberg K. Lopez Kostka S. Lorenz B. Regen T. Waisman A. von Stebut E. IL-17A/F in Leishmania major-resistant C57BL/6 mice.Exp Dermatol. 2019; 28: 321-323Crossref PubMed Scopus (4) Google Scholar). Only artificial overexpression of IL-17A in CD4+ T cells of C57BL/6 mice led to disease aggravation (Dietze-Schwonberg et al., 2019Dietze-Schwonberg K. Lopez Kostka S. Lorenz B. Regen T. Waisman A. von Stebut E. IL-17A/F in Leishmania major-resistant C57BL/6 mice.Exp Dermatol. 2019; 28: 321-323Crossref PubMed Scopus (4) Google Scholar); thus, it appears that in KitW-sh/KitW-sh mice, MC-associated decreased levels of IFN-γ are responsible for the worsening of the disease, whereas in the same mice on BALB/c background, IL-17A–dependent neutrophil recruitment dominates disease outcome. Most importantly, because MC-independent c-kit effects may also contribute to our findings, we reconstituted C.B6KitW-sh mice locally with MC by intradermal injection of 5 × 104 bone marrow‒derived MCs generated from BALB/c mice (Galand et al., 2016Galand C. Leyva-Castillo J.M. Yoon J. Han A. Lee M.S. McKenzie A.N.J. et al.IL-33 promotes food anaphylaxis in epicutaneously sensitized mice by targeting mast cells.J Allergy Clin Immunol. 2016; 138: 1356-1366Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar) into the ears. Reconstitution was confirmed by enumerating the MC in the ear skin at several time points (week 6 after infection; Figure 1b). Reconstituted mice were also infected with 1,000 metacyclic promastigotes (Figure 2a). Here, lesion volumes were comparable with those of BALB/c wild-type mice, confirming that the absence of skin MCs in C.B6KitW-sh mice—and not other c-kit‒related effects—is responsible for improved disease outcome (Figure 2a). In line with our findings, pharmacological activation of MC before L. major infection using compound 48/80 made BALB/c mice more resistant to infection, suggesting that modulation of MC function in genetically susceptible individuals can serve as a therapeutic approach (Romão et al., 2009Romão P.R. Da Costa Santiago H. Ramos C.D. De Oliveira C.F. Monteiro M.C. De Queiroz Cunha F. et al.Mast cell degranulation contributes to susceptibility to Leishmania major.Parasite Immunol. 2009; 31: 140-146Crossref PubMed Scopus (21) Google Scholar). Similar to our study, this effect was independent of IL-4. In contrast to studies using c-kit‒dependent MC deficiency as in our study, mice genetically lacking MC independent of c-kit by the introduction of the CPA3Cre allele (CpaCre-mice) showed no differences in the disease outcome after L. major infection compared with wild types. Like the controls, MC-deficient BALB/c Cpa3Cre mice suffered from more severe leishmaniasis than C57BL/6 Cpa3Cre mice (Paul et al., 2016Paul C. Wolff S. Zapf T. Raifer H. Feyerabend T.B. Bollig N. et al.Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice.Eur J Immunol. 2016; 46: 114-121Crossref PubMed Scopus (21) Google Scholar). Nevertheless, the differences in the route of infection, parasite strains, and inoculation doses may additionally contribute to this discrepancy in results (Dudeck et al., 2019Dudeck A. Köberle M. Goldmann O. Meyer N. Dudeck J. Lemmens S. et al.Mast cells as protectors of health.J Allergy Clin Immunol. 2019; 144: S4-S18Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). However, in both models, the adoptive transfer of MCs normalized the phenotype. Thus, studies with a side-by-side comparison of kit-dependent and kit-independent MC deletion mouse models are required to resolve this question. In summary, in contrast to our previous findings in MC-deficient C57BL/6 KitW-sh/KitW-sh mice (Dudeck et al., 2011Dudeck A. Suender C.A. Kostka S.L. von Stebut E. Maurer M. Mast cells promote Th1 and Th17 responses by modulating dendritic cell maturation and function.Eur J Immunol. 2011; 41: 1883-1893Crossref PubMed Scopus (103) Google Scholar; Maurer et al., 2006Maurer M. Lopez Kostka S. Siebenhaar F. Moelle K. Metz M. Knop J. et al.Skin mast cells control T cell-dependent host defense in Leishmania major infections.FASEB J. 2006; 20: 2460-2467Crossref PubMed Scopus (105) Google Scholar), genetic c-kit–dependent deletion of MC in susceptible BALB/c mice led to a better disease outcome by contributing to Th17-associated neutrophil recruitment to lesions (Lopez Kostka et al., 2009Lopez Kostka S. Dinges S. Griewank K. Iwakura Y. Udey M.C. von Stebut E. IL-17 promotes progression of cutaneous leishmaniasis in susceptible mice.J Immunol. 2009; 182: 3039-3046Crossref PubMed Scopus (157) Google Scholar; Tacchini-Cottier et al., 2000Tacchini-Cottier F. Zweifel C. Belkaid Y. Mukankundiye C. Vasei M. Launois P. et al.An immunomodulatory function for neutrophils during the induction of a CD4+ Th2 response in BALB/c mice infected with Leishmania major.J Immunol. 2000; 165: 2628-2636Crossref PubMed Scopus (229) Google Scholar). Clearly, our results help to understand the role of MC in L. major infections in susceptible mice, which will further lead to a better understanding of involved mechanisms leading to resistance or susceptibility in mice and humans. No datasets were generated or analyzed during this study. Kirsten Dietze-Schwonberg: http://orcid.org/0000-0001-7649-4754 Beate Lorenz: http://orcid.org/0000-0001-7880-6272 Ann-Kathrin Hartmann: http://orcid.org/0000-0001-8961-6458 Michael Stassen: http://orcid.org/0000-0001-6610-6439 Esther von Stebut: http://orcid.org/0000-0001-9802-9642 The authors state no conflict of interest. We thank Frank Siebenhaar and Marcus Maurer for helpful discussions. This work was funded by a grant from the Deutsche Forschungsgemeinschaft to EVS (SFB1292). Conceptualization: KDS, MS, EvS; Data Curation: KDS, BL, AKH; Formal Analysis: KDS, BL, MS, EVS; Writing - Original Draft Preparation: KDS, MS, EvS; Writing - Review and Editing: KDS, MS, EvS" @default.
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• W3043200126 date "2021-02-01" @default.
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• W3043200126 title "Mast Cell Deficiency Protects Susceptible BALB/c Mice from Progressive Murine Cutaneous Leishmaniasis" @default.
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