Intercellular Communication in Airway Epithelial Cell Regeneration: Potential Roles of Connexins and Pannexins

Abstract

Connexins and pannexins are transmembrane proteins that can form direct (gap junctions) or indirect (connexons, pannexons) intercellular communication channels. By propagating ions, metabolites, sugars, nucleotides, miRNAs, and/or second messengers, they participate in a variety of physiological functions, such as tissue homeostasis and host defense. There is solid evidence supporting a role for intercellular signaling in various pulmonary inflammatory diseases where alteration of connexin/pannexin channel functional expression occurs, thus leading to abnormal intercellular communication pathways and contributing to pathophysiological aspects, such as innate immune defense and remodeling. The integrity of the airway epithelium, which is the first line of defense against invading microbes, is established and maintained by a repair mechanism that involves processes such as proliferation, migration, and differentiation. Here, we briefly summarize current knowledge on the contribution of connexins and pannexins to necessary processes of tissue repair and speculate on their possible involvement in the shaping of the airway epithelium integrity.

Keywords: connexins; epithelial differentiation; epithelial repair; epithelial signaling; intercellular communication; lungs; pannexins.

Figure 1

Gene expression of connexin isoforms in well-differentiated primary cultures of human airway epithelial cells. Heat map showing raw count data of connexin (A) isoforms obtained by RNA-seq on primary cultures of human airway epithelial cells in 6 individuals [25]. The source data can be accessed from the NCBI Gene Expression Omnibus (GEO) with the accession number GSE127696. (B) Relative expression of connexin mRNAs in different airway epithelial cell types, as evaluated by integrating single-cell transcriptomic data from the atlas of the human respiratory system [14] and the multi-institute consortium study [26] carried out on human airway tissues.

Figure 2

Gene expression of pannexin isoforms in well-differentiated primary cultures of human airway epithelial cells. Heat map showing raw count data of pannexin (A) isoforms obtained by RNA-seq on primary cultures of human airway epithelial cells in 6 individuals [25]. The source data can be accessed from the NCBI Gene Expression Omnibus (GEO) with the accession number GSE127696. (B) Relative expression of Panx1 and Panx2 mRNAs in different airway epithelial cell types, as evaluated by integrating single-cell transcriptomic data from the atlas of the human respiratory system [14] and the multi-institute consortium study [26] carried out on human airway tissues.

Figure 3

Gene expression profile of connexins and pannexin isoforms in repairing primary human airway epithelial cells. Fold-change heat map of detected connexin (A) and pannexin mRNAs (B) in primary human airway epithelial cells at different times of wound repair normalized to the nonwounded condition (NW). pW = 24 h post wound, WC = wound closure, pWC = 48 h post wound closure. The data are from [25] and can be accessed from the NCBI Gene Expression Omnibus (GEO) with the accession number GSE127696.

Figure 4

Gene expression of purinergic receptors in well-differentiated primary human airway epithelial cells. Heat map showing raw count data of purinergic receptors obtained by RNA-seq on primary cultures of human airway epithelial cells in 6 individuals [25].

Figure 5

Hypothetical integrative scenario on the contribution of intercellular communication to airway epithelial regeneration. The blue box represents how connexins and pannexins, upon injury, could regulate proliferative and migratory signals through their channel-dependent and/or –inde-pendent function. The green box highlights the interplay between connexins and epithelial/mesenchymal markers in fine-tuning EMT/MET during the repair process. The orange box describes how connexins may ultimately be part of the barrier-stabilizing network through their physical and functional interaction with tight junctions, adherens junctions, and cytoskeleton components. + means positive action. ?: points to mechanisms requiring investigation. See text for details and abbreviations. The figure was created using pictures from Servier Medical Art. Servier Medical Art by Servier is licensed under a Creative Commons Attribution 3.0 Unported License (https://creativecommons.org/licenses/by/3.0/), accessed on 12 October 2023.