Microbial metabolite succinate activates solitary chemosensory cells in the human sinonasal epithelium.

Abstract

BACKGROUND:

Succinate, although most famous for its role in the Krebs cycle, can be released extracellularly as a signal of cellular distress, particularly in situations of metabolic stress and inflammation. Solitary chemosensory cells (SCCs) express SUCNR1, the succinate receptor, and modulate type 2 inflammatory responses in helminth and protozoal infections in the small intestine. SCCs are the dominant epithelial source of interleukin-25, as well as an important source of cysteinyl leukotrienes in the airway, and have been implicated as upstream agents in type 2 inflammation in chronic rhinosinusitis (CRS) and asthma.

METHODS:

In this study, we used scRNAseq analysis, live cell imaging of intracellular calcium from primary sinonasal air-liquid interface (ALI) cultures from 1 donor, and measure antimicrobial peptide release from 5 donors to demonstrate preliminary evidence suggesting that succinate can act as a stimulant of SCCs in the human sinonasal epithelium.

RESULTS:

Results from scRNAseq analysis show that approximately 10% of the SCC/ionocyte cluster of cells expressed SUCNR1 as well as a small population of immune cells. Using live cell imaging of intracellular calcium, we also demonstrate that clusters of cells on primary sinonasal ALI cultures initiated calcium-mediated signaling in response to succinate stimulation. Furthermore, we present evidence that primary sinonasal ALI cultures treated with succinate had increased levels of apical beta-defensin 2, an antimicrobial peptide, compared to treatment with a control solution.

CONCLUSION:

Overall, these findings demonstrate the need for further investigation into the activation of the sinonasal epithelium by succinate in the pathogenesis of CRS.

• Authors: Elizabeth A Sell, Li Hui Tan, Cailu Lin, John V Bosso, James N Palmer, Nithin D Adappa, Robert J Lee, Michael A Kohanski, Danielle R Reed, Noam A Cohen
• Journal: International forum of allergy & rhinology (Int Forum Allergy Rhinol) Vol. 13 Issue 8 Pg. 1525-1534 (08 2023) ISSN: 2042-6984 [Electronic] United States
• PMID: 36565436 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2022 ARS-AAOA, LLC.

Chemical References

• Succinic Acid
• Calcium
• Antimicrobial Peptides

Topics

• Humans
• Rhinitis
• Succinic Acid (metabolism)
• Calcium (metabolism)
• Epithelium (metabolism)
• Sinusitis
• Chronic Disease
• Inflammation
• Antimicrobial Peptides
• Epithelial Cells (metabolism)