Environmental Toxicants-Induced Immune Responses in the Olfactory Mucosa

Abstract

Olfactory sensory neurons (OSNs) are the receptor cells for the sense of smell. Although cell bodies are located in the olfactory mucosa (OM) of the nasal cavity, OSN axons directly project to the olfactory bulb (OB) that is a component of the central nervous system (CNS). Because of this direct and short connection from this peripheral tissue to the CNS, the olfactory system has attracted attention as a port-of-entry for environmental toxicants that may cause neurological dysfunction. Selected viruses can enter the OB via the OM and directly affect the CNS. On the other hand, environmental toxicants may induce inflammatory responses in the OM, including infiltration of immune cells and production of inflammatory cytokines. In addition, these inflammatory responses cause the loss of OSNs that are then replaced with newly generated OSNs that re-connect to the OB after inflammation has subsided. It is now known that immune cells and cytokines in the OM play important roles in both degeneration and regeneration of OSNs. Thus, the olfactory system is a unique neuroimmune interface where interaction between nervous and immune systems in the periphery significantly affects the structure, neuronal circuitry, and immunological status of the CNS. The mechanisms by which immune cells regulate OSN loss and the generation of new OSNs are, however, largely unknown. To help develop a better understanding of the mechanisms involved, we have provided a review of key research that has investigated how the immune response in the OM affects the pathophysiology of OSNs.

Type 2/Th2‐driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model

“…Nasal airflow reduction, edema‐induced compression of olfactory nerves, or hypersecretion of Bowman's glands with altered ion concentrations in the olfactory mucus likely contribute to reducing the sense of smell . It has also been suggested that inflammatory mediators could have direct neurotoxic actions on olfactory sensory neurons (OSNs) . OSNs with abnormal morphologies and potential functional defects, as well as higher numbers of immature neurons, suggesting an attempt at regeneration, have also been reported in CRS patients.…”

Cytokine profile in human olfactory cleft mucus and associated changes in olfactory function

“…The IL-1 receptor IL-1R is ubiquitously expressed in virtually all cell types and is a key signaling receptor for the IL-1 family of inflammatory cytokines (35). As an endogenous IL-1 receptor antagonist, IL-1RA may play critical roles in shutting down IL-1R signaling in the nasal respiratory tissues and the olfactory mucosa to inhibit allergen-and/or infection-induced inflammatory responses (7). The high levels of IL-1RA are likely needed to protect the tissues from inflammation-related injury.…”

“…Decades of exposure to air-borne environmental agents may also contribute to age-related olfactory loss (7). However, the molecular aspects of aging-associated olfactory loss in humans are not well understood.…”

“…Inflammation may play significant roles in chemosensory disorders (7)(8)(9)(10). Some diseases with robust inflammatory responses in the nose, such as upper respiratory infection and chronic rhinosinusitis, are strongly associated with olfactory loss (3,(11)(12)(13).…”

“…In addition, shown in animal studies, inflammation and some inflammatory cytokines induced in the olfactory mucosa inhibit neurogenesis and/or stimulate apoptosis of olfactory neurons (8,14,15). In the aging olfactory mucosa, cellular injuries and stress, resulting from life-long exposure to harmful chemicals, allergens, and pathogens, could stimulate inflammation (7). However, whether aging increases the levels of inflammatory cytokines in the human olfactory mucosa and whether any inflammatory markers are associated with age-related olfactory loss remain unclear.…”