Interferon gamma causes olfactory dysfunction without concomitant neuroepithelial damage

Abstract

Introduction Olfactory loss is a debilitating symptom of chronic rhinosinusitis (CRS). The pathophysiology of inflammatory olfactory dysfunction likely involves both conductive and sensorineural components. To study the interaction of CRS-associated inflammatory cytokines with the olfactory epithelium, a transgenic mouse model was developed that allows temporally-controlled local gene expression. Interferon-gamma (IFN-γ) is a prototypical Th1 cytokine linked to non-polypoid CRS, as well as sinonasal viral and bacterial infections. In this study, the effects of chronic IFN-γ expression on olfactory histology and function were investigated. Methods IFN-γ secretion by olfactory sustentacular cells was induced in the transgenic mouse. Viability and gross behavior were unaffected. Mice were sacrificed after 6 weeks of IFN-γ expression, and olfactory tissue was studied by histology, immunohistochemistry, and electro-olfactogram (EOG). Findings were compared with uninduced littermates. Results IFN-γ expression did not result in alteration of the normal histologic architecture of the neuroepithelium or lamina propria. However, EOG recordings demonstrated a significant decrease in odorant responses after IFN-γ expression. In addition, a marked increase in submucosal CD45-positive cells was observed, the majority of which were CD3 and CD4 positive lymphocytes. Conclusion Chronic IFN-γ expression in the mouse olfactory epithelium results in diminished odorant responsiveness, despite the absence of inflammatory tissue damage. This suggests a direct effect of IFN-γ on olfactory neuron function that may underlie olfactory loss in CRSsNP or viral infections. The infiltration of submucosal lymphocytes raises the possibility that other downstream cytokines also contribute to olfactory dysfunction.

Role of tissue eosinophils in chronic rhinosinusitis–associated olfactory loss

“…These effects have been previously reported for an array of cytokines that include tumor necrosis factor α (TNF‐α), IL‐6, and interferon γ (IFN‐γ) . The potential adverse effects of TNF‐α and IFN‐γ on olfactory neuron function and/or survival have been confirmed in recent animal studies . Likewise, Henkin et al .…”

Olfactory functions in patients with psoriasis vulgaris: correlations with the severity of the disease

“…In previous studies from mice models, it is reported that TNF-a inhibits olfactory regeneration [32] and directly causes physiologic dysfunction of olfactory neurons [29]. Also, chronic IFN-c expressions in the mouse have been caused olfactory dysfunction [20]. On the other hand, elevated IL-6 (as a pro-inflammatory cytokine) levels were found in plasma, saliva, and nasal mucus in patients with hyposmia recently [9].…”

Olfactory and middle meatal cytokine levels correlate with olfactory function in chronic rhinosinusitis

“…Several cytokines have neurotoxic potential, and it is conceivable that the olfactory dysfunction in CRS patients may be mediated in part by their effects on olfactory neuronal cell function, apoptosis, differentiation, and proliferation. Recent evidence from transgenic mouse models have supported this olfactory inflammation hypothesis, with local overexpression of proinflammatory cytokines such as tumor necrosis factor‐α (TNF‐α) and interferon‐γ, resulting in inhibition of olfactory neuron function, turnover, or survival . Likewise, a recent study in patients with CRS found that quantitative olfactory function may be inversely associated with olfactory mucus levels of interleukin (IL)‐5 …”

“…Recent evidence from transgenic mouse models have supported this olfactory inflammation hypothesis, with local overexpression of proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) and interferon-c, resulting in inhibition of olfactory neuron function, turnover, or survival. [20][21][22][23] Likewise, a recent study in patients with CRS found that quantitative olfactory function may be inversely associated with olfactory mucus levels of interleukin (IL)-5. 24 Despite the putative importance of proinflammatory cytokines in olfactory function, studies to clarify the role of cytokines in human olfactory tissue have been limited.…”