Allergic inflammation is a primary pathological feature of many debilitating diseases . Among the numerous active mediators and cytokines that modulate initiation and progression of allergic inflammation, histamine is distinctly potent [1, 2]. Typically, the storage of histamine is restricted to mast cells and circulating basophils [2, 3]. The cardinal pathway of histamine release involves the attachment of IgE-bound allergens to high-affinity FcεRI receptors on mast cells and the crosslinking of adjacent IgE molecules by allergens [1, 2]. Subsequent receptor clustering leads to a complex cascade of intracellular Ca2+ signaling resulting from increased activity of phospholipase C (PLC), generation of diacylglycerol (DAG) (activating PKC) and inositol 1,4,5-trisphosphate (IP3) which mobilizes the ER Ca2+ store and participates in final histamine secretion from mast cells. Activation of histamine receptors (H1, H2, H3 and H4) greatly influences inflammatory responses .
Aside from inducing acute allergic inflammatory responses, histamine also mediates chronic phase progression by augmenting the secretion of pro-inflammatory cytokines such as IL-1α, IL-1β, and IL-6 as well as chemokines like RANTES [1, 4]. Consequential pathologies are expressed in many systems encompassing ocular, airway, skin and GI tracts . Associated disorders may include asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis, urticaria, anaphylaxis and food allergies [1, 4, 5]. Possible clinical symptoms include itchiness, increased vascular permeability, edema, leukocyte infiltration, bronchoconstriction and mucus hypersecretion [1, 4, 5]. Therefore, any disturbance to the immunological and/or homeostatic control of histamine release can potentially intensify inflammation leading to health problems.
Recently, numerous epidemiological studies have suggested that pollution associated airborne particulate matter (PM) can aggravate allergic inflammatory responses. Classical examples of allergies indicate that people with asthma and rhinitis are more susceptible to the short term acute effects of particle exposure [6–8]. In line with epidemiological studies, results from animal models also demonstrated that ultrafine particles (one of the major components of PM) can modulate asthmatic responses by exacerbating pulmonary inflammation and airway hyper-responsiveness [9–11]. In an atopic, dermatitis-like, skin lesion mouse model, exposure to titanium dioxide nanoparticles (TiO2 NPs) was found to worsen symptoms by elevating proinflammatory molecules in the skin and increasing serum levels of IgE and histamine . At the same time, exposure to environmental tobacco smoke has been found to increase the risks of rhinoconjunctivitis and allergic conjunctivitis [13, 14]. Moreover, Kulig et al reported that prenatal and postnatal exposure to environmental tobacco smoke in children (< 3 yrs old) was associated with sensitization to food allergens . Despite NPs' ability to potentiate allergic responses, the role that histamine plays in mediation is not clear. More importantly, whether NPs can directly modulate histamine release from mast cells without allergen sensitization remains elusive.
TiO2 NPs have been extensively utilized in the nano-technological and pharmaceutical arenas and are one of the main components in many household commodities and personalized products [16, 17]. The enormous annual global production of TiO2 broadens the possibilities of occupational and environmental exposures . As a common constituent of PM10, TiO2 NPs are widely known for their potential hazardous effects, which manifest biologically via inflammatory responses . TiO2 NPs size, surface area and crystalline structure ascribe cellular nanotoxicity [20–23]. In addition to respiratory inhalation, NPs can enter the human body via alternative routes such as: direct penetration through skin, ingestion and injection . Animal studies have shown that intra-tracheally instilled TiO2 and other NPs can possibly transmigrate from lung to systemic circulation [25–27]. Upon entering blood circulation, NPs can infiltrate multiple organs, potentially directly stimulating mast cells, a critical effector, exacerbating pathological consequences . As such, TiO2 NPs were selected as ideal model particles for our study.
Previously, we have demonstrated that TiO2 NPs can trigger a cascade of cytosolic Ca2+ signaling leading to mucin secretion . In the present study, we aim to investigate the impact of NPs on histamine secretion from RBL-2H3 mast cells. We hypothesize that TiO2 NPs can directly induce histamine release without prior allergen sensitization via a Ca2+-mediated pathway.