Mast cell accumulation drives allergy-driven chronic pain responses in outbred mice

Abstract

Abstract We are building novel outbred mouse models of a poorly understood yet prevalent vulvar pain condition – localized, provoked vulvodynia – that affects a substantial proportion of 18–60 year old women. Epidemiologic studies have shown a surprising and increased risk for developing this condition in women with a history of skin and airway allergies. We show that repeated exposures to low doses of the common contact irritant haptens oxazolone or dinitrofluorobenzene on the genital skin of mice produce sustained painful sensitivity to touch as well as a non-normative accumulation of mast cells and an overgrowth of cutaneous nerves in the affected tissue – changes that are also seen in vulvar biopsies taken from women diagnosed with vulvodynia providing the first evidence of biological plausibility for the immunological underpinnings of this chronic pain condition. In addition to laboratory haptens, we show that the hapten methylisothiazolinone (a common cosmetic preservative found in soaps, shampoos, and feminine hygiene products) can induce these responses suggesting that this ubiquitous environmental exposure might be a possible immunological trigger of hitherto unexplained genital pain conditions that affect many women. We have further characterized infiltrating T cells at the allergic site to show that FoxP3+ regulatory CD4 T cells and CD103+ resident memory CD8 T accumulate at these sites as well. Our mouse models provide new tools to both dissect allergy driven pain conditions as well as test novel therapies targeting immune cells and mechanisms for the management and treatment of these debilitating disorders.