Mast cells are key components of the immune system, where they help orchestrate the inflammatory response. Aberrant mast cell activation is linked to a variety of allergic diseases, including
asthma,
eczema,
rhinitis, and nasal polyposis, which in combination affect up to 20% of the population in industrialized countries. On activation, mast cells release a variety of signals that target the bronchi and vasculature and recruit other immune cells to the inflammatory site. Prominent among such signals are the cysteinyl
leukotrienes, a family of potent proinflammatory
lipid mediators comprising
leukotriene C(4) (LTC(4)), LTD(4), and LTE(4). LTC(4), the parent compound, is secreted from mast cells following Ca(2+) influx through store-operated
calcium release-activated
calcium (
CRAC) channels. Here, we show that activated mast cells release a paracrine signal that evokes Ca(2+) signals in spatially separate resting mast cells. The paracrine signal was identified as a
cysteinyl leukotriene because 1) RNAi knockdown or pharmacological block of the
5-lipoxygenase enzyme prevented activated mast cells from stimulating resting cells. 2) Block of
cysteinyl leukotriene type I receptors on resting mast cells with the clinically prescribed receptor antagonist
montelukast prevented their activation by active mast cells. 3) RNAi knockdown of
cysteinyl leukotriene type I receptors on resting cells prevented them from responding to the paracrine signal derived from activated mast cells. 4) Purified LTC(4) evoked Ca(2+) signals in mast cells that were identical to those triggered by the paracrine signal. Low levels of stimulus intensity released sufficient levels of
leukotriene to activate resting cells.
Leukotriene secretion still occurred
tens of minutes after stimulation, suggesting a role as a long-lasting trigger in mast cell activation. Stimulation of the
cysteinyl leukotriene receptor activated
CRAC channels and evoked prominent store-operated Ca(2+) entry. This resulted in further
cysteinyl leukotriene production, triggering a positive feedback cascade. Acutely isolated mast cells from patients with
allergic rhinitis exhibited store-operated Ca(2+) influx through
CRAC channels and responded to cysteinyl
leukotrienes. Histological analysis of samples taken from patients revealed clustering of mast cells, often located within 20 microm of each other, a distance sufficient for paracrine signaling by
leukotrienes to operate effectively. We conclude that a positive-feedback cascade involving
CRAC channels and cysteinyl
leukotrienes constitute a novel mechanism for sustaining mast cell activation.