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Danger signaling and allergic inflammation

Environmental allergens that interact with the airway epithelium can activate cellular stress pathways that lead to the release of danger signals known as alarmins. The mechanisms of alarmin release are distinct from Damage-Associated Molecular Patterns (DAMPs), which typically escape from cells following loss of plasma membrane integrity. Oxidative stress represents a form of allergen-induced cellular stress that stimulates oxidant-sensing mechanisms coupled to pathways which facilitate alarmin mobilization and transport across the plasma membrane. Accordingly, allergen-evoked cellular stress can elicit a hierarchy of alarmin signaling responses from the airway epithelium that trigger local innate immune reactions, impact adaptive immunity and exacerbate diseases including asthma and other chronic inflammatory conditions that affect airway function.   

Alternaria stimulated ATP secretion activates calcium conducting P2X receptors leading to a sustained increase in intracellular [Ca2+].

Alternaria allergens stimulate ATP secretion

Alternaria alternata is a common fungus that is highly allergenic and known to trigger asthmatic responses in sensitized asthma patients. Exposure of the airway epithelium to Alternaria spores induces oxidative stress leading to ATP release by activating voltage-dependent anion channels (VDAC-1) and stimulating exocytosis of ATP-containing membrane vesicles. Extracellular ATP functions as a primary alarmin that initiates type 2 immune responses. We are presently investigating the molecular mechanisms that underlie allergen-evoked ATP secretion with the goal of identifying potential targets for development of new pharmacotherapies that prevent or significantly reduce allergic inflammation.

Alternaria allergens induce gDNA fragmentation and release into the extracellular media of cultured human bronchial epithelial cells or bronchoalveolar lavage fluid in mouse airways. Created with biorender.com