Scientific Oral Presentations: Pathophysiology and Mechanisms
ARS055 - Succinate activates solitary chemosensory cells (SCCs) in the nose
Friday, April 29, 2022
11:34 AM – 11:40 AM CT
Location: Landmark C
Li Hui Tan, PhD; Cailu Lin, PhD; John Bosso, MD; James N. Palmer, MD, FARS; Nithin D. Adappa, MD, FAR; Robert J. Lee, PhD; Michael Kohanski, MD; Danielle Reed, Associate Director; Noam A. Cohen, MD, PhD, FARS; Ralph Butler, Endowed Professor for Medical Research
Medical Student University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania
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 or as a microbial metabolite. Increased extracellular levels of succinate as well as activation of the succinate receptor, SUCNR1, have been implicated in a variety of pathophysiological processes, primarily through pro-inflammatory signaling pathways. Intestinal tuft cells (analogous to nasal solitary chemosensory cells and brush cells) express SUCNR1 and succinate activates tuft cells yielding local type 2 inflammatory responses in the small intestine. Tuft cells/SCCs are the dominant epithelial source of interleukin-25 as well as an important source of cysteinyl leukotrienes in the airway which have been implicated in type 2 inflammation in nasal polyps and asthma. Additionally, taste receptors expressed on SCCs regulate release of antimicrobial peptides. In this study, we demonstrate that succinate can act as a stimulant of human nasal SCCs. Results from sc-RNAseq analysis show that approximately 10% of the SCCs express SUCNR1. Using live cell calcium imaging, we demonstrate that discrete cells in primary sinonasal air liquid interface (ALI) cultures initiate calcium-mediated signaling in response to succinate stimulation with similar kinetics to traditional SCCs agonists (denatonium benzoate). Furthermore, primary sinonasal ALI cultures treated with succinate evinced increased levels of apical antimicrobial peptide beta-defensin 2, compared to treatment with a control solution. Overall, these findings demonstrate the need for further investigation into the activation of the sinonasal epithelium by succinate in the pathogenesis of CRS.