The activation of hippocampus microglia in the occurrence of airway hyperresponsiveness comorbidity anxiety

Airway hyperresponsiveness (AHR) is often associated with mood disorders such as anxiety and depression which makes the airway symptoms more complicated and refractory. However, the underlying mechanisms remain unclear. This study investigated whether this was related to the activation of microglia in the hippocampus. Female Balb/c mice were randomly assigned into an AHR model induced by ovalbumin (OVA) and an anxiety model induced by chronic restraint stress (CRS). Anxiety-like behavior was assessed by open field test, elevated plus maze and tail suspension test. Airway resistance following methacholine inhalation was measured by using the FlexiVent apparatus. Hematoxylin and eosin, periodic acid-Schiff as well as Masson trichrome were performed to evaluate inflammatory cell infiltration in the lung tissue. In addition, the status of microglia in the hippocampus was evaluated by immunofluorescence, while the activation of inflammation signaling pathway was assessed by Western blots. Compared with the Control group, mice in OVA and CRS groups exhibited higher airway resistance, spent less time in the center area of the open field and the open arms of the elevated plus maze, and showed increased immobility time in the tail suspension test. Microglia in hippocampus exhibited pronounced morphological alterations, increased expression of activation markers Iba1 and CD86, and upregulation of the NLRP3 inflammasome pathway. Minocycline treatment significantly reduced the airway resistance and anxiety-like behavior in OVA mice, while also inhibiting activation of the NLRP3 inflammasome pathway. This study provides evidence for the comorbidity between AHR and anxiety, potentially mediated by hippocampal microglial activation and the NLRP3/Caspase-1/IL-1β pathway. These findings enhance our understanding of the underlying mechanisms, and offer potential targets for treating AHR-related anxiety.