ABSTRACT
Mast cells (MCs) play critical roles in the establishment of allergic diseases. We recently demonstrated an unexpected, proinflammatory role for IL-10 in regulating MC responses. IL-10 enhanced MC activation and promoted IgE-dependent responses during food allergy. However, whether these effects extend to IgE-independent stimuli is not clear. In this article, we demonstrate that IL-10 plays a critical role in driving IL-33-mediated MC responses. IL-10 stimulation enhanced MC expansion and degranulation, ST2 expression, IL-13 production, and phospho-relA upregulation in IL-33-treated cells while suppressing TNF-α. These effects were partly dependent on endogenous IL-10 and further amplified in MCs coactivated with both IL-33 and IgE/Ag. IL-10's divergent effects also extended in vivo. In a MC-dependent model of IL-33-induced neutrophilia, IL-10 treatment enhanced MC responsiveness, leading to suppression of neutrophils and decreased TNF-α. In contrast, during IL-33-induced type 2 inflammation, IL-10 priming exacerbated MC activity, resulting in MC recruitment to various tissues, enhanced ST2 expression, induction of hypothermia, recruitment of eosinophils, and increased MCPT-1 and IL-13 levels. Our data elucidate an important role for IL-10 as an augmenter of IL-33-mediated MC responses, with implications during both allergic diseases and other MC-dependent disorders. IL-10 induction is routinely used as a prognostic marker of disease improvement. Our data suggest instead that IL-10 can enhance ST2 responsiveness in IL-33-activated MCs, with the potential to both aggravate or suppress disease severity depending on the inflammatory context.
Subject(s)
Food Hypersensitivity , Mast Cells , Humans , Mast Cells/metabolism , Interleukin-10/metabolism , Tumor Necrosis Factor-alpha/metabolism , Immunoglobulin E/metabolism , Interleukin-33/metabolism , Interleukin-13/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Inflammation/metabolism , Cell DegranulationSubject(s)
Disease Models, Animal , Food Hypersensitivity , Interleukin-1 Receptor-Like 1 Protein , Interleukin-4 , Mast Cells , Animals , Mast Cells/immunology , Mast Cells/metabolism , Mice , Food Hypersensitivity/immunology , Interleukin-4/metabolism , Interleukin-1 Receptor-Like 1 Protein/metabolism , Signal TransductionABSTRACT
IgE-mediated mast cell (MC) activation is a critical component of allergic responses to oral Ags. Several T cell-derived cytokines have been shown to promote MC reactivity, and we recently demonstrated a critical role for the cytokine IL-10 in mediating MC responses during food allergy. In this study, we further validate the role of IL-10 using Ab-mediated IL-10 depletion. IL-10 neutralization significantly attenuated MC responses, leading to decreased MC accumulation and activation, as well as inhibition of MC-mediated symptoms such as allergic diarrhea. This was accompanied by decreased Th2 cytokine gene expression, attenuated systemic T cell responses, and fewer CD4 T cells, B cells, and MCs in the spleen. Our data further confirm the role of IL-10 in driving MC responses and suggest that IL-10-responsive MCs may constitute an important player in allergic responses.