Dataset Information

Mast cell degranulation impairs pneumococcus clearance in mice via IL-6 dependent and TNF-? independent mechanisms.

ABSTRACT:

Background

Mast cells participate in immune responses by releasing potent immune system modifiers via degranulation. Due to currently reported controversial roles of mast cells in Streptococcus pneumoniae infections, this study aimed to determine the role and mechanism of mast cells in clearing S. pneumoniae in mice.

Methods

In vivo mouse model of mast cell degranulation established by administration of C48/80 was evaluated for the influences of mast cell degranulation on bacterial colonization and inflammation. In vitro model was established to observe the influences of mast cell degranulation on phagocytic and bactericidal functions of neutrophils and macrophages. IL-6 null and TNF-? null mice on the C57BL/6 background were used to investigate the effects of inflammatory factors released by mast cell degranulation on bacterial clearance.

Results

Mast cell degranulation increased IL-6 and TNF-? levels and immune cell numbers in nasal lavage fluid, and inhibited the bactericidal function of macrophages and neutrophils in vitro. It decreased the number of neutrophils and macrophages recruited to respiratory tract after S. pneumoniae challenge and inhibited the clearance of S. pneumoniae in mice. After pretreatment with C48/80, S. pneumoniae loads were significantly lower in IL-6 null mice than in wild type mice, while no differences were observed between TNF-? null and wild type mice.

Conclusions

Mast cell degranulation can cause inflammation and impair immune cell recruitment to respiratory tract after S. pneumoniae challenge. Products of mast cell degranulation including IL-6 decreased the bactericidal function of neutrophils and macrophages. Through these mechanisms, mast cell degranulation inhibited clearance of S. pneumoniae in mice.

SUBMITTER: Yang J

PROVIDER: S-EPMC6479162 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

Mast cell degranulation impairs pneumococcus clearance in mice <i>via</i> IL-6 dependent and TNF-α independent mechanisms.

Yang Jing J Wang Jichao J Zhang Xuemei X Qiu Yulan Y Yan Jurong J Sun Si S He Yujuan Y Yin Yibing Y Xu Wenchun W

The World Allergy Organization journal 20190420 4

<h4>Background</h4>Mast cells participate in immune responses by releasing potent immune system modifiers <i>via</i> degranulation. Due to currently reported controversial roles of mast cells in <i>Streptococcus pneumoniae</i> infections, this study aimed to determine the role and mechanism of mast cells in clearing <i>S. pneumoniae</i> in mice.<h4>Methods</h4><i>In vivo</i> mouse model of mast cell degranulation established by administration of C48/80 was evaluated for the influences of mast ce ...[more]

PMID: 31044024

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Project description:BackgroundMast cells derive from hematopoietic cell precursors and participate in tissue allergic, immune, and inflammatory processes. They secrete many mediators, including preformed TNF, in response to allergic, neuropeptide, and environmental triggers. However, regulation of mast cell degranulation is not well understood.ObjectiveWe investigated the role of mitochondrial dynamics in degranulation of human cultured mast cells.MethodsHuman umbilical cord blood-derived mast cells (hCBMCs) and Laboratory of Allergic Diseases 2 (LAD2) mast cells were examined by confocal and differential interference contrast microscopy during activation by IgE/antigen and substance P (SP). Mast cells in control and atopic dermatitis (AD) skin were evaluated by transmission electron microscopy. LAD2 cells were pretreated with mitochondrial division inhibitor, a dynamin-related protein 1 (Drp1) inhibitor, and small interfering RNA for Drp1, which is necessary for mitochondrial fission and translocation. Calcineurin and Drp1 gene expression was analyzed in stimulated LAD2 cells and AD skin biopsies.ResultsStimulation of hCBMCs with IgE/antigen or LAD2 cells with SP leads to rapid (30 minutes) secretion of preformed TNF. Degranulation is accompanied by mitochondrial translocation from a perinuclear location to exocytosis sites. Extracellular calcium depletion prevents these effects, indicating calcium requirement. The calcium-dependent calcineurin and Drp1 are activated 30 minutes after SP stimulation. Reduction of Drp1 activity by mitochondrial division inhibitor and decrease of Drp1 expression using small interfering RNA inhibit mitochondrial translocation, degranulation, and TNF secretion. Mitochondrial translocation is also evident by transmission electron microscopy in skin mast cells from AD biopsies, in which gene expression of calcineurin, Drp1, and SP is higher than in normal skin.ConclusionHuman mast cell degranulation requires mitochondrial dynamics, also implicated in AD.