Expression of Transient Receptor Potential C6 Channels in Human Lung Macrophages

Abstract

Chronic obstructive pulmonary disease (COPD) is associated with pulmonary inflammation with increased numbers of macrophages located in the parenchyma. These macrophages have the capacity to mediate the underlying pathophysiology of COPD; therefore, a better understanding of their function in chronic inflammation associated with this disease is vital. Ion channels regulate many cellular functions; however, their role in macrophages is unclear. This study examined the expression and function of transient receptor potential (TRP) channels in human macrophages. Human alveolar macrophages and lung tissue macrophages expressed increased mRNA and protein for TRPC6 when compared with monocytes and monocyte-derived macrophages. Moreover, TRPC6 mRNA expression was significantly elevated in alveolar macrophages from patients with COPD compared with control subjects. There were no differences in mRNA for TRPC3 or TRPC7. Although mRNA for TRPM2 and TRPV1 was detected in these cells, protein expression could not be determined. Fractionation of lung-derived macrophages demonstrated that TRPC6 protein was more highly expressed by smaller macrophages compared with larger macrophages. Using whole-cell patch clamp electrophysiology, TRPC6-like currents were measured in both macrophage subpopulations with appropriate biophysical and basic pharmacological profiles. These currents were active under basal conditions in the small macrophages. These data suggest that TRPC6-like channels are functional on human lung macrophages, and may be associated with COPD.

TRPC6 channel translocation into phagosomal membrane augments phagosomal function

“…Numerous studies (12)(13)(14)(15) have suggested TRP channels as potential targets for the development of therapies in pulmonary inflammation because of their abundant and diverse cellular expression throughout the respiratory tree. Although TRPC6 channels have been previously identified in lung macrophages and shown to be up-regulated in COPD, their precise role in the pathophysiology of the disease is yet to be determined (16). Perhaps more relevant to our study, a TRPC6-mediated Ca 2+ influx is increased in human CF airway epithelial cells, possibly because of a functional association between CFTR and TRPC6 that is lost in CF (17), with unknown consequences.…”

“…(R)-roscovitine-activated currents were similar in selectivity to those reported (24) for the heterologously expressed recombinant human TRPC6 channels: nonselective cation channels that are Ca 2+ -permeable. Expression of TRPC6 channels has been reported in human AMs and is known to be elevated in AMs originating from patients who are smokers and from those diagnosed with COPD (16). TRPC6 channels are gated through direct interaction with diacylglycerol (DAG) or its membrane permeant analog 1-oleoyl-2-acetyl-sn-glycerol (OAG).…”

Identification of a distinct glucocorticosteroid-insensitive pulmonary macrophage phenotype in patients with chronic obstructive pulmonary disease

“…Lung tissue macrophages were isolated as described previously using discontinuous Percoll density gradients 28 confirmed using the Reastain Quick-Diff Kit (Genatur, London, UK) according to manufacturers' instructions, and anti-CD68 staining as previously described 29 . Additional detail is provided in an online data supplement.…”

Identification and Validation of Larixyl Acetate as a Potent TRPC6 Inhibitor

“…In the pulmonary vascular system, TRPC6 has gained considerable attention from several studies that demonstrated its involvement in hypoxia-induced pulmonary vasoconstriction (HPV) (Weissmann et al, 2006;Fuchs et al, 2011;Tabeling et al, 2015) and idiopathic pulmonary hypertension (Yu et al, 2004(Yu et al, , 2009, and also its role in contributing to lung edema formation (Samapati et al, 2012;Weissmann et al, 2012). In addition, TRPC6 expression in lung macrophages (Finney-Hayward et al, 2010) and in bronchial smooth muscle cells may provide a link between TRPC6 and pathophysiological mechanisms that induce or aggravate chronic or allergic obstructive airway diseases (Sel et al, 2008). In the kidney, TRPC6 is expressed in podocytes that constitute the glomerular filtration membranes (Reiser et al, 2005).…”