Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2

Abstract

Certain biogenic amines, such as 2-PEA, TYR, or T1AM, modulate blood pressure, cardiac function, brain monoaminergic systems, and olfaction-guided behavior by specifically interacting with members of a group of rhodopsin-like receptors, TAAR. A receptor that is absent from olfactory epithelia but had long been identified in the brain and a variety of peripheral tissues, TAAR1 has been found recently in blood B cells, suggesting a functional role of TAAR1 in these cells. With the present study, we have set out to clarify the expression and functional roles of TAAR in different isolated human blood leukocyte types. Here, we report the functional expression of TAAR1 and its closest relative TAAR2 in blood PMN and T and B cells. Both receptors are coexpressed in a subpopulation of PMN, where they are necessary for the chemosensory migration toward the TAAR1 ligands 2-PEA, TYR, and T1AM, with EC50 values of 0.43 ± 0.05 nM, 0.52 ± 0.05 nM, and 0.25 ± 0.04 nM, respectively. The same amines, with similar potencies, triggered cytokine or Ig secretion, in purified blood T or B cells, respectively. Notably, 2-PEA regulated mRNA expression of 28 T cell function-related genes, above all of the CCL5. In siRNA-guided experiments, TAAR1 and TAAR2 proved to be necessary for amine-induced blood leukocyte functions. In summary, our results demonstrate that biogenic amines potently regulate blood cell functions via TAAR1 and TAAR2 and open the perspective of their specific pharmacological modulation.

Trace Amines and Their Receptors

“…This has subsequently been verified by numerous laboratories (Mühlhaus et al, 2014;Cöster et al, 2015;Chiellini et al, 2017), with 3IT also shown to act as an agonist at TAAR2 (Babusyte et al, 2013;Cichero and Tonelli, 2017) and as an inverse agonist at TAAR5 (Dinter et al, 2015c). 3IT is promiscuous, however, and also interacts with high affinity at a 2 -adrenoceptors (Regard et al, 2007;Dinter et al, 2015b), b-adrenergic receptors (Meyer and Hesch, 1983;Kleinau et al, 2011;Dinter et al, 2015a), muscarinic acetylcholine receptors (Laurino et al, 2016), transient receptor potential cation channel subfamily M member 8 ion channels (Khajavi et al, 2015;Lucius et al, 2016), various monoamine and organic anion transporters (Snead et al, 2007;Panas et al, 2010), and molecular target(s) within mitochondria, including the F 1 -F 0 ATP synthase (Cumero et al, 2012) and possibly complex III (Venditti et al, 2011).…”

“…As previously noted, PEA and TYR may be released from activated platelets (D'Andrea et al, 2003) and have been reported to be positive chemotactic agents for leukocytes (Babusyte et al, 2013). The joint regulation of TAAR1 and TAAR2 is important from this aspect, as the chemoattractant response of leukocytes toward TAAR1-selective agonists appears to be dependent on the presence of both TAAR1 and TAAR2, possibly due to the need for heterodimerization of the two (Babusyte et al, 2013). From this perspective, the TAAR1/TAAR2 axis may provide a molecular explanation for the well known immune dysfunction that is associated with amphetamine-like drugs of abuse (Boyle and Connor, 2010;Sriram et al, 2015), many of which are TAAR1 agonists.…”

“…This includes the D cells of the stomach Revel et al, 2013;Adriaenssens et al, 2015;Raab et al, 2015), pancreatic b cells (Regard et al, 2007;Revel et al, 2013;Raab et al, 2015), and intestinal enterochromaffin mucosal cells (Kidd et al, 2008;Ito et al, 2009;Revel et al, 2013;Raab et al, 2015) of both rodents and humans. Multiple groups have also reported the presence of TAAR1 mRNA and protein in various populations of mouse and human leukocytes (D'Andrea et al, 2003;Nelson et al, 2007;Wasik et al, 2012;Babusyte et al, 2013), and the presence of TAAR1 protein in breast tissue was suggested very recently (Vattai et al, 2017), although in this latter instance no details on the cell type(s) in which staining was observed were provided. Furthermore, …”

“…Immunomodulatory Effects. Not only is TAAR1 differentially expressed between leukocyte populations (Babusyte et al, 2013), but its expression, along with that of TAAR2, is increased at both mRNA and protein levels after leukocyte activation Wasik et al, 2012;Table 4). As previously noted, PEA and TYR may be released from activated platelets (D'Andrea et al, 2003) and have been reported to be positive chemotactic agents for leukocytes (Babusyte et al, 2013).…”

“…Not only is TAAR1 differentially expressed between leukocyte populations (Babusyte et al, 2013), but its expression, along with that of TAAR2, is increased at both mRNA and protein levels after leukocyte activation Wasik et al, 2012;Table 4). As previously noted, PEA and TYR may be released from activated platelets (D'Andrea et al, 2003) and have been reported to be positive chemotactic agents for leukocytes (Babusyte et al, 2013). The joint regulation of TAAR1 and TAAR2 is important from this aspect, as the chemoattractant response of leukocytes toward TAAR1-selective agonists appears to be dependent on the presence of both TAAR1 and TAAR2, possibly due to the need for heterodimerization of the two (Babusyte et al, 2013).…”