Background: Pulmonary neuroendocrine cells (PNEC) are rare airway epithelial cells that have recently gained attention as potential amplifiers of allergic asthma. However, studying PNEC function in humans has been challenging due to a lack of cell isolation methods, and little is known about human PNEC function in response to asthma‐relevant stimuli. Here we developed and characterized an in vitro human PNEC model and investigated the neuroendocrine response to extracts of the common aeroallergen house dust mite (HDM). Methods: PNEC‐enriched cultures were generated from human induced pluripotent stem cells (iPNEC) and primary bronchial epithelial cells (ePNEC). Characterized PNEC cultures were exposed to HDM extract, a volatile chemical odorant (Bergamot oil), or the bacterial membrane component, lipopolysaccharide (LPS), and neuroendocrine gene expression and neuropeptide release determined. Results: Both iPNEC and ePNEC models demonstrated similar baseline neuroendocrine characteristics and a stimuli‐specific modulation of gene expression. Most notably, exposure to HDM but not Bergamot oil or LPS, leads to dose‐dependent induction of the CGRP encoding gene, CALCB, and corresponding release of the neuropeptide. HDM‐induced CALCB expression and CGRP release could be inhibited by a protease‐activated receptor 1 (PAR1) antagonist or protease inhibitors and was mimicked by a PAR1 agonist. Conclusions: We have characterized a novel model of PNEC‐enriched human airway epithelium and utilized this model to demonstrate a previously unrecognized role for human PNEC in mediating a direct neuroendocrine response to aeroallergen exposure.

The essential role of the lungs in gas exchange necessitates exposure to possible threats from a dynamic external environment. To protect life-critical functions the airways contain multiple systems that monitor the inhaled environment and elicit appropriate defensive responses. As such the airways represent a key sensory surface with multiple signaling pathways to the brain. Despite the presence of rich and diverse bacterial communities in both upper and lower airways, the respiratory tract has been relatively overlooked compared to the gut regarding its potential as an interface between microbes and the central nervous system. This review draws attention to the respiratory system, specifically the nasal cavity and lungs, and the evidence supporting a microbiota-airway-brain axis. We highlight the olfactory system and the role of the lungs as a sensory organ, monitoring the inhaled environment, as clear examples of airway-brain communication and identify how these communication pathways can be engaged by microbes. We also outline the relationship between the airways and mental health and present the case that the nasal and lung microbiota should be considered alongside that of the gut as potential influencers of brain function, mood, and behavior.

Mast cells are heterogeneous, tissue-resident immune sentinels best known for their roles in allergy and peripheral inflammation. The discovery of mast cells within the meninges and brain parenchyma over a century ago raised enduring questions regarding their function in the central nervous system (CNS), their ontogeny, and distinction from peripheral counterparts. Brain mast cells are sparse and predominantly located in perivascular niches rather than forming dense aggregates, a feature that has made them difficult to study. Nevertheless, accumulating evidence implicates mast cells in diverse aspects of CNS physiology and pathology, including regulation of blood–brain barrier (BBB) permeability and neurovascular function, as well as immune surveillance in contexts of infection and injury. The ability of mast cells to communicate with neighboring glial and neuronal networks suggests potential roles in modulating neural activity, development, and behavior, although this dimension remains incompletely understood. Much of the foundational literature predates advanced immunological tools, contributing to persistent misconceptions regarding the identity and significance of brain mast cells. In this review, we outline the history of research investigating this enigmatic aspect of mast cell biology, clarifying what is known, what remains speculative, and how emerging insights may help redefine the boundaries between classical immunology and neuroscience.

Postpartum depression (PPD) is a mood disorder that affects the ability of mothers to engage with and care for their infants. Stress exposure is known to be a major predisposing factor for PPD, while immune factors such as T regulatory cells (Tregs) are also hypothesized to influence the development of the disorder. Here we assessed limited nesting (LN) in mice, with or without depletion of Tregs through anti‐CD25 antibody treatment, as a potential model to investigate the relationship between stress and the immune system in PPD. Dams and their pups were exposed to LN from post‐natal day 3–10 and maternal behaviour was evaluated over this period followed by assessment of maternal self‐care using the splash test. Gene expression in selected brain regions and the peripheral lymphocyte profile were also assessed. LN exposure led to a significant increase in aggressive behaviour towards the pups and altered grooming in the splash test. These effects on behaviour were associated with brain region specific changes in expression of several genes related to depression and maternal behaviour and with increased levels of Tregs in the periphery. When LN was combined with anti‐CD25 antibody treatment, there were further deficits in nursing behaviour and changes in the brain circuitry related to lactation and stress. Our study indicates that LN in mice may be a useful model for studying neuroimmune relationships in certain aspects of PPD. Our data also suggest that post‐partum regulatory immune changes may mitigate effects of stress on brain circuitry associated with maternal behaviour, lactation and stress.

Background Pulmonary neuroendocrine cells (PNEC) are rare airway epithelial cells that have recently gained attention as potential amplifiers of allergic asthma. However, studying PNEC function in humans has been challenging due to a lack of cell isolation methods and little is known about human PNEC function in response to asthma relevant stimuli. Here we developed and characterized an in vitro human PNEC model and investigated the neuroendocrine response to extracts of the common aeroallergen house dust-mite. (HDM). Methods PNEC enriched cultures were generated from human induced pluripotent stem cells (iPNEC) and primary bronchial epithelial cells (ePNEC). Characterized PNEC cultures were exposed to HDM extract, a volatile chemical odorant (Bergamot oil), or the bacterial membrane component, lipopolysaccharide (LPS) and neuroendocrine gene expression and neuropeptide release determined. Results Both iPNEC and ePNEC models demonstrated similar baseline neuroendocrine characteristics and a stimuli specific modulation of gene expression. Most notably, exposure to HDM but not Bergamot oil or LPS, lead to dose dependent induction of the CGRP encoding gene, CALCB, and corresponding release of the neuropeptide. HDM induced CALCB expression and CGRP release could be inhibited by a protease activated receptor 1 (PAR1) antagonist or protease inhibitors and was mimicked by a PAR1 agonist. Conclusions We have characterized a novel model of PNEC enriched human airway epithelium and utilized this model to demonstrate a previously unrecognized role for human PNEC in mediating a direct neuroendocrine response to aeroallergen exposure and highlighting CGRP production by these cells as a potential therapeutic target in allergic asthma.