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Single-cell analysis of mast cell degranulation induced by airway smooth muscle-secreted chemokines.

ABSTRACT: Asthma is a chronic inflammatory disease characterized by narrowed airways, bronchial hyper-responsiveness, mucus hyper-secretion, and airway remodeling. Mast cell (MC) infiltration into airway smooth muscle (ASM) is a defining feature of asthma, and ASM regulates the inflammatory response by secreting chemokines, including CXCL10 and CCL5. Single cell analysis offers a unique approach to study specific cellular signaling interactions within large and complex signaling networks such as the inflammatory microenvironment in asthma.Carbon-fiber microelectrode amperometry was used to study the effects of ASM-secreted chemokines on mouse peritoneal MC degranulation.MC degranulation in response to CXCL10 and CCL5 was monitored at the single cell level. Relative to IgE-mediated degranulation, CXCL10- and CCL5-stimulated MCs released a decreased amount of serotonin per granule with fewer release events per cell. Decreased serotonin release per granule was correlated with increased spike half-width and rise-time values.MCs are directly activated by ASM-associated chemokines. CXCL10 and CCL5 induce less robust MC degranulation compared to IgE- and A23187-stimulation. The kinetics of MC degranulation are signaling pathway-dependent, suggesting a biophysical mechanism of regulated degranulation that incorporates control over granule trafficking, transport, and docking machinery.The biophysical mechanisms, including variations in number of exocytotic release events, serotonin released per granule, and the membrane kinetics of exocytosis that underlie MC degranulation in response to CXCL10 and CCL5 were characterized at the single cell level. These findings clarify the function of ASM-derived chemokines as instigators of MC degranulation relative to classical mechanisms of MC stimulation.

SUBMITTER: Manning BM

PROVIDER: S-EPMC4516622 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Single-cell analysis of mast cell degranulation induced by airway smooth muscle-secreted chemokines.

Manning Benjamin M BM Meyer Audrey F AF Gruba Sarah M SM Haynes Christy L CL

Biochimica et biophysica acta 20150515 9

<h4>Background</h4>Asthma is a chronic inflammatory disease characterized by narrowed airways, bronchial hyper-responsiveness, mucus hyper-secretion, and airway remodeling. Mast cell (MC) infiltration into airway smooth muscle (ASM) is a defining feature of asthma, and ASM regulates the inflammatory response by secreting chemokines, including CXCL10 and CCL5. Single cell analysis offers a unique approach to study specific cellular signaling interactions within large and complex signaling network ...[more]

PMID: 25986989

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Project description:BACKGROUND AND PURPOSE: ??-Adrenoceptor agonists are important therapeutic agents in the treatment of asthma and chronic obstructive pulmonary disease. The regular use of these drugs has been associated with proasthmatic-like changes that limit their efficacy and increase the risk of severe adverse reactions. We investigated whether the peroxisome-proliferator-activated receptor (PPAR)? agonist rosiglitazone modulated salbutamol-induced ??-adrenoceptor desensitization in vivo and in vitro. EXPERIMENTAL APPROACH: An in vivo model of homologous ??-adrenoceptor desensitization, established in guinea-pigs by administering salbutamol continuously, was used to study the ability of rosiglitazone to prevent ??-adrenoceptor tolerance. In vitro experiments on human bronchial smooth muscle cells were performed to increase the clinical relevance of the study. KEY RESULTS: In tracheal smooth muscle tissues from desensitized animals, we observed a decrease in the protective effect of salbutamol on carbachol-induced contraction, a hyperresponsiveness to cholinergic stimuli, a modest underexpression of ??-adrenoceptor gene and a marked decrease in ?-adrenoceptor number, relative to control values. Treatment with rosiglitazone preserved salbutamol relaxant activity, mitigated carbachol hyperresponsiveness and partially restored ??-adrenoceptor binding sites in tracheal tissues from homologously desensitized animals. The highly selective PPAR? agonist, GW1929, reproduced the effect of rosiglitazone, in vivo. In vitro ??-adrenoceptor desensitization decreased salbutamol-mediated cAMP production, without affecting forskolin responses and ??-adrenoceptor expression. Rosiglitazone and 15-deoxy-?¹²(,)¹?-prostaglandin J? restored salbutamol sensitivity in homologously desensitized cells. CONCLUSIONS AND IMPLICATIONS: These data suggest a potential pharmacodynamic interaction between PPAR? agonists and salbutamol on airway smooth muscle responsiveness, supporting the therapeutic potential of this combination in chronic airway disease.

Dataset Information

Single-cell analysis of mast cell degranulation induced by airway smooth muscle-secreted chemokines.

Publications

Single-cell analysis of mast cell degranulation induced by airway smooth muscle-secreted chemokines.

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