Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling

Abstract

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 ~ 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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Acknowledgements

This study was supported by National Institutes of Health grants (R01DC016309, R21AI137484). Content is solely the responsibility of the authors and does not represent official views of the National Institutes of Health. The authors thank J. Riley (University of Pennsylvania Human Immunology Core, supported by P30-CA016520 and P30-AI045008) for access to monocytes and M. Victoria (University of Pennsylvania) for excellent assistance with MΦ culture and molecular biology and helpful comments on the manuscript. We thank D. McMahon and L.E. Kuek (University of Pennsylvania) for assistance with qPCR. We thank N. Cohen (University of Pennsylvania) for sharing reagents. The authors have no conflicts of interest to declare.

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Gopallawa, I., Freund, J.R. & Lee, R.J. Bitter taste receptors stimulate phagocytosis in human macrophages through calcium, nitric oxide, and cyclic-GMP signaling. Cell. Mol. Life Sci. 78, 271–286 (2021). https://doi.org/10.1007/s00018-020-03494-y

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Keywords

  • Live cell imaging
  • Innate immunity
  • Quorum sensing
  • Airway epithelium
  • G-protein-coupled receptors