Chronic allergic lung inflammation negatively influences neurobehavioral outcomes in mice

Abstract

Background Asthma is a major public health problem worldwide. Emerging data from epidemiological studies show that allergies and allergic diseases may be linked to anxiety, depression and cognitive decline. However, little is known about the effect of asthma, an allergic lung inflammation, on cognitive decline/behavioral changes. Therefore, we investigated the hypothesis that allergic lung inflammation causes inflammation in the brain and leads to neurobehavioral changes in mice. Methods Wild-type C57BL/6J female mice were sensitized with nasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. A series of neurocognitive tests for anxiety and/or depression were performed before and after the intranasal HDM administration. After the behavior tests, tissues were harvested to measure inflammation in the lungs and the brains. Results HDM-treated mice exhibited significantly increased immobility times during tail suspension tests and significantly decreased sucrose preference compared with PBS controls, suggesting a more depressed and anhedonia phenotype. Spatial memory impairment was also observed in HDM-treated mice when assessed by the Y-maze novel arm tests. Development of lung inflammation after 6 weeks of HDM administration was confirmed by histology, bronchoalveolar lavage (BAL) cell count and lung cytokine measurements. Serum pro-inflammatory cytokines and Th2-related cytokines levels were elevated in HDM-sensitized mice. In the brain, the chemokine fractalkine was increased in the HDM group. The c-Fos protein, a marker for neuronal activity, Glial Fibrillary Acidic Protein (GFAP) and chymase, a serine protease from mast cells, were increased in the brains from mice in HDM group. Chymase expression in the brain was negatively correlated with the results of sucrose preference rate in individual mice. Conclusions 6 weeks of intranasal HDM administration in mice to mimic the chronic status of lung inflammation in asthma, caused significant inflammatory histological changes in the lungs, and several behavioral changes consistent with depression and altered spatial memory. Chymase and c-Fos proteins were increased in the brain from HDM-treated mice, suggesting links between lung inflammation and brain mast cell activation, which could be responsible for depression-like behavior.

Peripheral inflammation and neurocognitive impairment: correlations, underlying mechanisms, and therapeutic implications

“…Chronic allergic lung inflammation or systemic inflammation due to chronic obstructive pulmonary disease (COPD) may adversely affect neurobehavior, and the evidence here supports the central nervous effects of peripheral inflammation ( Pelgrim et al, 2019 ; Kanaya et al, 2022 ). The current definition of the “lung-brain axis” focuses more on the complex regulatory relationship between the microbiome, the lungs, and the brain, i.e., the microbiome located in the lungs can influence the both organs and participate in the regulation of respiratory and neurological diseases, and conversely, respiratory and neurological diseases can lead to alterations in the structure and diversity of the lung microbiome ( Hosang et al, 2022 ).…”

Regulation of Microglial Signaling by Lyn and SHIP-1 in the Steady-State Adult Mouse Brain

“…Although serum cytokines were not measured in this study, we and others have previously shown that young adult SHIP-1−/− mice on a C57BL/6 background exhibit increased circulating cytokines, such as IFNγ, TNFα, IL-4, IL-6, G-CSF, and GM-CSF [12,88]. This may alter the integrity of the blood-brain barrier and lead to increased cytokine levels in the brain [89,90], ultimately enhancing neuroimmune responses and obscuring the effect of the intrinsic loss of SHIP-1 activity in microglia. Therefore, future studies utilizing a combination of conditional knockout models and ex vivo cell culture experiments are needed to fully define the intrinsic role of SHIP-1 in microglia.…”

Brain response in asthma: the role of “lung-brain” axis mediated by neuroimmune crosstalk

“…(4) Whether the relationship between asthma and olfactory dysfunction is mediated or directly related by nasal diseases lacks relevant evidence. A summary of changes in brain network/activity, mediators, and related brain regions involved in the response of the brain in asthma is shown in Table 2 ( 12 , 21 , 31 , 34 , 37 , 42 , 44 , 49 , 53 , 56 , 58 , 59 , 68 , 70 , 72 , 74 , 78 , 82 , 97 , 113 , 114 ).…”

“…In addition to inflammatory factors, Kanaya et al found elevated levels of vascular endothelial growth factor (VEGF) in the blood of asthmatic mice and high concentrations of c-FOS protein, and glial fibrillary acidic protein (GFAP) deposition was detected in their brain regions, which is known to increase the permeability of the BBB. In addition, GFAP is a typical astrocyte injury marker, whereas c-FOS protein expression elevates when mast cells are activated in the brain, thereby indicating that inflammatory factors may infiltrate brain regions through the destruction of the BBB to activate neurons and mast cells in the brain, impair astrocyte function, disrupt mood regulation, and produce depressive disorders (82,83). Depression and anxiety disorders, as common internalization disorders, involve many overlapping regulatory mechanisms in the pathogenesis of asthma, such as the activation of brain regions by oxidative stress, damage to brain structure by inflammatory factors, and feedback regulation of the HPA axis.…”

“…in the lung may lead to up-regulation of VEGF, c-FOS protein and GFAP expression in brain regions, and mast cell activation in brain regions may mediate the generation of depression-like behavior by affecting the function of related brain regions. Kanaya A, et al(82)…”