CXCL13 is expressed in a subpopulation of neuroendocrine cells in the murine trachea and lung

Abstract

The conducting airways are lined by distinct cell types, comprising basal, secretory, ciliated, and rare cells, including ionocytes, solitary cholinergic chemosensory cells, and solitary and clustered (neuroepithelial bodies) neuroendocrine cells. Airway neuroendocrine cells are in clinical focus since they can give rise to small cell lung cancer. They have been implicated in diverse functions including mechanosensation, chemosensation, and regeneration, and were recently identified as regulators of type 2 immune responses via the release of the neuropeptide calcitonin gene-related peptide (CGRP). We here assessed the expression of the chemokine CXCL13 (B cell attracting chemokine) by these cells by RT-PCR, in silico analysis of publicly available sequencing data sets, immunohistochemistry, and immuno-electron microscopy. We identify a phenotype of neuroendocrine cells in the naïve mouse, producing the chemokine CXCL13 predominantly in solitary neuroendocrine cells of the tracheal epithelium (approx. 70% CXCL13+) and, to a lesser extent, in the solitary neuroendocrine cells and neuroepithelial bodies of the intrapulmonary bronchial epithelium (< 10% CXCL13+). In silico analysis of published sequencing data of murine tracheal epithelial cells was consistent with the results obtained by immunohistochemistry as it revealed that neuroendocrine cells are the major source of Cxcl13-mRNA, which was expressed by 68–79% of neuroendocrine cells. An unbiased scRNA-seq data analysis of overall gene expression did not yield subclusters of neuroendocrine cells. Our observation demonstrates phenotypic heterogeneity of airway neuroendocrine cells and points towards a putative immunoregulatory role of these cells in bronchial-associated lymphoid tissue formation and B cell homeostasis.

Correlation of Neuroendocrine Differentiation with a Distinctively Suppressive Immune Microenvironment in Gastric Cancer

“…Compared to SLOs, conditions for TLS formation are not so strict, and they can form themselves even in the absence of LTi cells but with the help of various types of cells that express CXCL13, CCL19, or CCL21 [41][42][43]. Hence, given the significantly elevated expression of CXCL13, CCL19, and CCL21 in GC-NED and the findings that neuroendocrine cells produced CXCL13 [44], an attractive microenvironment for B and T cells probably formed by high-level LTo cell-related cytokines, which might contribute to the B-and T-cell accumulation in GC-NED, providing a solid base for the marked TLS increase. However, the identification and confirmation of LTo cells and their functions are needed in the future.…”

Neuroendocrine cells initiate protective upper airway reflexes

“…Pulmonary NE cells were enriched for osteopontin ( Spp1 ) and cocaine- and amphetamine-regulated transcript ( Cartpt ), whereas tracheal and laryngeal NE cells were enriched for the B cell chemoattractant Cxcl13 (fig. S1D) ( 22 , 33 ). Moreover, only a subset of tracheal and laryngeal NE cells expressed calcitonin gene–related peptide (CGRP) or serotonin, whereas all pulmonary NE cells were CGRP-positive and serotonergic (fig.…”

Neuroimmune Interaction: A Widespread Mutual Regulation and the Weapons for Barrier Organs

“…They are compact structures within the mucous membrane of the airway and are innervated by vagal afferent fibers. The apical surface of NEB is exposed to the airway, responding to a series of stimuli such as hypoxia, hypercapnia, mechanical stretching, norepinephrine, etc., and producing several bioactive mediators, including bell bombesin, CGRP, and 5-HT ( Table 3 ) ( De Virgiliis and Di Giovanni, 2020 ; Mahmoud et al, 2021 ). Sensory nerves from the dorsal root ganglion can not only release neuromedin U (NMU) to promote the proliferation of ILC2 and type 2 inflammatory response ( Cardoso et al, 2017 ; Klose et al, 2017 ; Wallrapp et al, 2017 ), but also secrete neuromedin B (NMB) to inhibit ILC2 response, eosinophilia, and mucus production in the stage of allergic inflammation and worm infection, forming a bidirectional regulation ( Chen et al, 2020b ; Inclan-Rico et al, 2020 ).…”