CCL7-CCR3 signaling mediates olfactory dysfunction in a mouse model of allergic rhinitis

Allergic rhinitis (AR) is a prevalent chronic upper airway inflammatory disorder. Olfactory dysfunction (OD) in AR patients represents a frequent and burdensome complication that significantly compromises quality of life. While the pathogenesis of AR-associated OD remains incompletely characterized, emerging evidence points to olfactory bulb (OB) microglial neuroinflammation as a crucial contributor. C-C motif chemokine ligand 7 (CCL7) is consistently upregulated in AR nasal mucosa and has been documented to drive microglial inflammation. However, its expression and function in OB microglia remain undefined. This study aimed to investigate the specific role of CCL7 in OB microglia and its potential contribution to AR-associated OD, with the goal of providing new mechanistic insights and potential intervention targets.

An ovalbumin (OVA)-induced murine AR-associated OD model was established and validated through behavioral, serological, and histopathological analyses. CCL7 and C-C chemokine receptor type 3 (CCR3) expression profiles in OB and nasal mucosa were evaluated by qPCR, ELISA, and immunofluorescence colocalization with microglial markers. The therapeutic efficacy of intranasal CCL7 inhibition was assessed using Bindarit over a sustained intervention period. The specificity of the CCL7-CCR3 axis was further validated by intranasal exogenous CCL7 administration in naive mice and stereotaxic injection of the CCR3-specific antagonist SB-328437 into the OB of AR mice with established OD. In vitro studies employed co-culture with allergen-stimulated nasal epithelial and microglial cells, with or without CCR3 antagonist-pretreatment.

CCL7 expression was significantly elevated in OB of AR-associated OD mice, correlating positively with behavioral indices of OD. CCR3 was the only significantly upregulated CCL7 receptor in OB in this model, selectively localized to activated microglia. Intranasal Bindarit progressively improved olfactory function in AR mice, with marked improvement first observed at week 8 of treatment, with concomitant reduced CCL7 and neuroinflammatory mediators in OB. In contrast, intranasal exogenous CCL7 administration in naive mice recapitulated OD and upregulated these neuroinflammatory markers. Conversely, CCR3-specific antagonism with SB-328437 in the OB partially restored olfactory function in AR mice with established OD. In vitro, allergen-stimulated nasal epithelial cells secreted CCL7 that activated microglial cells through CCR3, an effect partially reversed by CCR3 antagonist.

The CCL7-CCR3 signaling axis links nasal allergic inflammation to OB microglial neuroinflammation and consequent OD in AR, identifying a promising therapeutic target for AR-associated OD.