Mast cells have no impact on cutaneous leishmaniasis severity and related Th2 differentiation in resistant and susceptible mice

Abstract

The genus leishmania comprises different protozoan parasites which are causative agents of muco-cutaneous and systemic, potentially lethal diseases. After infection with the species Leishmania major, resistant mice expand Th1 cells which stimulate macrophages for Leishmania destruction. In contrast, susceptible mice generate Th2 cells which deactivate macrophages, leading to systemic spread of the pathogens. Th-cell differentiation is determined within the first days, and Th2 cell differentiation requires IL-4, whereby the initial IL-4 source is often unknown. Mast cells are potential sources of IL-4, and hence their role in murine leishmaniasis has previously been studied in mast cell-deficient Kit mutant mice, although these mice display immunological phenotypes beyond mast cell deficiency. We therefore readdressed this question by infecting Kitindependent mast cell-deficient mice that are Th1 (C57BL/6 Cpa Cre ) or Th2 (BALB/c Cpa Cre ) prone with L. major. Using different parasite doses and intra-or subcutaneous infection routes, the results demonstrate no role of mast cells on lesion size development, parasite load, immune cell phenotypes expanding in draining lymph nodes, and cytokine production during murine cutaneous leishmaniasis. Thus, other cell types such as ILCs or T cells have to be considered as primary source of Th2-driving IL-4. Additional supporting information may be found in the online version of this article at the publisher's web-site Keywords

Unimpaired Responses to Vaccination With Protein Antigen Plus Adjuvant in Mice With Kit-Independent Mast Cell Deficiency

“…Our study adds to a long list of cases in which results in Kit mutant mouse strains did not reproduce in one of the novel mouse strains with Kit-independent selective MC deficiency but otherwise normal immune system, despite reported reversion of phenotypes of Kit mutants by reconstitution with in vitro differentiated MCs (31, 32, 34, 35, 37, 39, 40, 42, 44–46) [reviewed in Ref. (38, 41, 43)].…”

No Role for Mast Cells in Obesity-Related Metabolic Dysregulation

“…Of note, the discrepancy between Kit mutant mice and novel models of mast cell deficiency with unperturbed Kit function emerging in the analyses of diet-induced metabolic dysregulation is an addition to the already long list of cases in which key findings in Kit mutant mice were not reproduced in novel mast cell-deficient mouse strains with normal Kit function (11, 17, 20, 28, 31–37). Collectively, overwhelming evidence accumulated over the past few years that Kit mutant mice are unreliable as models of mast cell deficiency even if observed phenotypes can be reversed by reconstitution with in vitro -differentiated mast cells.…”

IgE and mast cells in host defense against parasites and venoms

“…Upon infection with L. major , Th1 cells in resistant mice activate macrophages, which is thought to promote destruction of the parasite whereas Th2 cells in susceptible mice inhibit macrophages and thereby favor the systemic dissemination of the pathogens. Studies in c- kit -independent MC-deficient mice that are either resistant (Th1 prone C57BL/6- Cpa3 Cre/+ ) or susceptible (Th2 prone BALB/c- Cpa3 Cre/+ ) to Leishmaniasis detected no role for MCs in the development of lesion size, parasite burden, cytokine production or immune responses in cutaneous leishmaniasis in mice [119]. …”