Several studies on humans and rodents have shown that the intranasal or nebulized inhalation in allergen-sensitized animals induced avoidance behavior and activated limbic brain areas [8, 9, 32, 33]. OVA or pollen-induced AR rats produced TH2 cytokines in the olfactory bulb and prefrontal cortex but not in the temporal cortex and hypothalamus, and increased brain activity was observed by functional MRI . Asthma induces activation of the microglias in the hippocampus and prefrontal cortex, elevated levels of TNF-α and IL-1β, and a significant loss of neurons in the brain . In the brain responses observed in allergic asthma, atopic dermatitis and multiple sclerosis, the levels of CCL11 increase, which promote eosinophil infiltration and subsequent neuronal damage in the affected area, followed by facilitation of the migration of microglias and ROS production, which ultimately enhance neurotoxicity induced by glutamate [34–36]. Additionally, the choroid plexus is an important structure of the ventricle with blood-brain barrier (BBB) permeability, which has a high level of expression of IL-4Rα. Macrophages of the choroid plexus that respond to IL-4 can release pro-inflammatory cytokines, which then leak into the brain to promote the microglia to produce a second wave of cytokines . Endothelin-1 produced by inflammatory tissue may increase BBB permeability and activate microglia expressing endothelin receptor B through the damaged BBB . Other hypotheses cite the role of IL-1β in allergic reactions, which activates the hypothalamic-pituitary-adrenal (HPA) axis, stimulates the release of cortisol and serotonin, and leads to mood disorders . This study also showed that AR-induced OD was closely related to neuroinflammation of the olfactory bulb. The expression of microglia marker protein CD11b, TNF-α, IL-1β and IL-6 in the olfactory bulbs were significantly increased in the AR mice with OD, which is similar to the findings in the hippocampus . However, the mechanism of allergen-induced damage to the olfactory bulb is not clear.
Numerous studies have shown that TLR4 is a key molecule that regulates the immune response during CNS infection and injury . After activation in the brain, TLR4 binds to MyD88 to relieve the inhibitory effect of IκB on NF-κB, promote NF-κB nuclear translocation, stimulate inflammation-related gene expression, and promote the synthesis and release of TNF-α, IL-1β and IL-6 [26–28]. Our research found that the dopamine D2 receptor agonist quinpirole inhibited the expression of TLR4 and downstream signal molecules in the olfactory bulb, and the release of inflammatory cytokines. Similar to these results, quinpirole suppressed the expression of TLR4/NF-κB pathway in PD mice by increasing the expression of βArr2, thereby preventing dopaminergic neuron degeneration . In addition, the regulatory effect of dopamine D2 receptor on neuroinflammation is also related to the mechanisms, such as NLRP3 inflammasome, renin-angiotensin system (RAS) and αB-crystallin. For example, the selective dopamine D2 receptor agonist LY171555 inhibited the activation of NLRP3 inflammasomes in the substantia nigra pars compacta of PD mice, thereby further controling the assembly process of the inflammasomes . L-DOPA suppressed the production of angiotensinogen in astrocytes through the dopamine D2 receptor, thereby inhibiting microglia-mediated inflammation and neuronal oxidative stress caused by excessive activation of RAS . Furthermore, quinpirole reduceed the level of pro-inflammatory mediators in the substantia nigra of PD mice by increasing the expression of αB-crystallin . This study also suggests that dopamine D2 receptor activation can reduce the TLR4/NF-κB-dependent release of TNF-α, IL-1β and IL-6 in the microglia and alleviate the inflammatory response of the olfactory bulb.
Recent studies have shown that the microglia releases the pro-inflammatory cytokines TNF-α and IL-1β to participate in the regulation of AMPAR trafficking, which is a key link in inducing neuroinflammatory damage [29–31]. The AMPAR trafficking results in intracellular Ca2+ overload, triggering a series of neurotoxic cascades such as mitochondrial damage, oxidative stress, and cell death [43, 44]. In a cervical spinal cord contusion model, the number of GluR1-containing AMPARs at the ipsilateral synapse increased after injury. In vivo nanoinjection of TNF-α into the ventral horn of the spinal cord resulted in increased GluR1 and decreased GluR2 at extrasynaptic and synaptic plasma membrane sites . In subsequent studies, the expression of the GluR1 subunit was increased in human NT2-N neurons exposed to TNF-α, leading to an increased susceptibility to kainate-induced necrosis, which was related to the A-Smase/NF-𝜅B pathway . Similar findings were observed in hippocampal neurons and lumbar motor neurons, in which TNF-α or IL-1β increased the surface expression of GluR1-containing AMPAR, accompanied by a significant increase in AMPAR-mediated excitatory postsynaptic currents [16, 47]. IL-1β promote the release of NOS and presynaptic glutamate, and ultimately lead to enhanced AMPAR activity . In addition, IL-1β in the brain is involved in microglia-related inflammatory pain and leads to the depolarization of paraventricular nucleus neurons or the membrane hyperpolarization of hypothalamic neurons, which is associated with abnormal AMPAR activation . Our results found that the activation of the dopamine D2 receptor inhibited the release of TNF-α, IL-1β and IL-6, accompanied with increased GluR1 and decreased GluR2, thereby alleviating the excitotoxicity mediated by AMPARs in the olfactory bulb.
In summary, inhibiting neuroinflammation is a promising strategy in the treatment of neurological diseases. For example, quinpirole prevents neuroinflammation-mediated dopaminergic neuron degeneration in PD  and reduces microglia-mediated inflammation . After the occurrence of intracerebral hemorrhage (ICH) or PD, exogenous quinpirole inhibit neuroinflammation and improve the outcome of the nervous system [23, 42]. The dopamine D2 receptor agonist bromocriptine significantly inhibited the hyperactivity of glial cells and reduced the production of TNF-α in the spinal cord of amyotrophic laternal sclerosis (ALS), thereby preventing the loss of motor neurons [50, 51]. Therefore, the dopamine D2 receptor may be an effective target to improve the neuroinflammation in the olfactory bulb, and ultimately help to develop drugs for the treatment of AR with olfactory dysfunction.