Repeated dermal application of the common preservative methylisothiazolinone triggers local inflammation, T cell influx, and prolonged mast cell-dependent tactile sensitivity in mice

Abstract

Occupational exposure to toxic chemicals increases the risk of developing localized provoked vulvodynia—a prevalent, yet poorly understood, chronic condition characterized by sensitivity to touch and pressure, and accumulation of mast cells in painful tissues. Here, we topically sensitized female ND4 Swiss mice to the common household and industrial preservative methylisothiazolinone (MI) and subsequently challenged them daily with MI or acetone and olive oil vehicle on the labiar skin. MI-challenged mice developed significant, persistent tactile sensitivity and long-lasting local accumulation of mast cells alongside early, transient increases in CD4 + and CD8 + T cells, eosinophils, neutrophils, and increases in pro-inflammatory cytokines. Therapeutic administration of imatinib, a c-Kit inhibitor known to inhibit mast cell survival, led to reduced mast cell accumulation and alleviated tactile genital pain. We provide the first pre-clinical evidence of dermal MI-induced mast-cell dependent pain and lay the groundwork for detailed understanding of these intersections between MI-driven immunomodulation and chronic pain.

Immune mechanisms in vulvodynia: key roles for mast cells and fibroblasts

“…In a follow-up study, repeated daily MI exposures for 10 days on the labial skin of previously sensitized mice resulted in mast cell accumulation and remarkably persistent tactile sensitivity for up to 70 days, long past the resolution of overt inflammation indicating possible central sensitization of the nervous system. Intraperitoneal treatment with imatinib, which targets protein kinase c-Kit expressed on mast cells, prevented mast cell accumulation and abrogated tactile sensitivity ( Kline et al., 2020 ). We derived vaginal fibroblast lines from sensitized mice exposed to 10 applications of MI or saline vehicle in the vaginal canal; fibroblasts derived from MI-challenged canals produced higher levels of IL-6 compared to those derived from saline-challenged canals when exposed to bacterial lipopolysaccharides or zymosan in vitro , mirroring the behavior of fibroblasts derived from vulvodynia patients ( Blum et al., 2020 ).…”

“…Despite these exceptions, as shown in multiple pre-clinical studies of vulvodynia discussed above (Arriaga-Gomez et al, 2019;Kline et al, 2020;Awad-Igbaria et al, 2022), therapies that reduced mast cell accumulation and activation also abrogated vulvar pain. Falsetta and colleagues found that injecting exogenous pro-resolving mediators reduced prostaglandin E2 production in fibroblasts from vulvodynia biopsies (Falsetta et al, 2021).…”

“…Fibroblasts derived from the vestibular tissues of vulvodynia patients showed amplified inflammatory responses to yeast antigens in vitro ( Falsetta et al., 2015 ). Repeated yeast infections ( Awad-Igbaria et al., 2022 ) and multiple exposures to irritant allergens ( Landry et al., 2017 ) or a common chemical preservative ( Arriaga-Gomez et al., 2019 ; Kline et al., 2020 ) produced persistent vulvar sensitivity to pressure along with mast cell accumulation and hyperinnervation in rodent models of vulvodynia. In this review, we discuss these studies and other lines of evidence implicating innate sensing and dysregulated immune responses in the pathology of vulvodynia and other chronic pain conditions.…”

Exploring Localized Provoked Vulvodynia: Insights from Animal Model Research

“…Inflammation-based models, where vulvodynia is induced using agents such as Candida, zymosan, and Complete Freund's Adjuvant (CFA), highlighting the role of inflammatory processes in the development of vulvodynia [1,[11][12][13][14][15][16][17][18]]. 2.…”

“…Allergy-induced models, which utilize allergic reactions to substances like oxazolone (OX) or methylisothiazolinone (MI) to mimic the condition, shedding light on the potential involvement of allergic responses in vulvodynia [16][17][18][19].…”