Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 78, Issue 1, Pages 271-286Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-020-03494-y
Keywords
Live cell imaging; Innate immunity; Quorum sensing; Airway epithelium; G-protein-coupled receptors
Categories
Funding
- National Institutes of Health [R01DC016309, R21AI137484, P30-CA016520, P30-AI045008]
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Bitter taste receptors T2Rs in human macrophages activate specific signaling pathways to promote physiological responses, such as nitric oxide generation and phagocytosis. These findings provide new insights into the immune recognition role of T2Rs in the immune system.
Bitter taste receptors (T2Rs) are GPCRs involved in detection of bitter compounds by type 2 taste cells of the tongue, but are also expressed in other tissues throughout the body, including the airways, gastrointestinal tract, and brain. These T2Rs can be activated by several bacterial products and regulate innate immune responses in several cell types. Expression of T2Rs has been demonstrated in immune cells like neutrophils; however, the molecular details of their signaling are unknown. We examined mechanisms of T2R signaling in primary human monocyte-derived unprimed (M0) macrophages (M Phi s) using live cell imaging techniques. Known bitter compounds and bacterial T2R agonists activated low-level calcium signals through a pertussis toxin (PTX)-sensitive, phospholipase C-dependent, and inositol trisphosphate receptor-dependent calcium release pathway. These calcium signals activated low-level nitric oxide (NO) production via endothelial and neuronal NO synthase (NOS) isoforms. NO production increased cellular cGMP and enhanced acute phagocytosis similar to threefold over 30-60 min via protein kinase G. In parallel with calcium elevation, T2R activation lowered cAMP, also through a PTX-sensitive pathway. The cAMP decrease also contributed to enhanced phagocytosis. Moreover, a co-culture model with airway epithelial cells demonstrated that NO produced by epithelial cells can also acutely enhance M Phi phagocytosis. Together, these data define M Phi T2R signal transduction and support an immune recognition role for T2Rs in M Phi cell physiology.
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