Abstract
BackgroundChronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells. NK cells are an essential innate immune cell, responsible for recognising and inducing apoptosis of tumour and virus infected cells. Calcium is an essential component in mediating this cellular function. Transient Receptor Potential Melastatin 3 (TRPM3) cation channels have an important regulatory role in mediating calcium influx to help maintain cellular homeostasis. Several single nucleotide polymorphisms have been reported in TRPM3 genes from isolated peripheral blood mononuclear cells, NK and B cells in patients with CFS/ME and have been proposed to correlate with illness presentation. Moreover, a significant reduction in both TRPM3 surface expression and intracellular calcium mobilisation in NK cells has been found in CFS/ME patients compared with healthy controls. Despite the functional importance of TRPM3, little is known about the ion channel function in NK cells and the epiphenomenon of CFS/ME. The objective of the present study was to characterise the TRPM3 ion channel function in NK cells from CFS/ME patients in comparison with healthy controls using whole cell patch-clamp techniques.MethodsNK cells were isolated from 12 age- and sex-matched healthy controls and CFS patients. Whole cell electrophysiology recording has been used to assess TRPM3 ion channel activity after modulation with pregnenolone sulfate and ononetin.ResultsWe report a significant reduction in amplitude of TRPM3 current after pregnenolone sulfate stimulation in isolated NK cells from CFS/ME patients compared with healthy controls. In addition, we found pregnenolone sulfate-evoked ionic currents through TRPM3 channels were significantly modulated by ononetin in isolated NK cells from healthy controls compared with CFS/ME patients.ConclusionsTRPM3 activity is impaired in CFS/ME patients suggesting changes in intracellular Ca2+ concentration, which may impact NK cellular functions. This investigation further helps to understand the intracellular-mediated roles in NK cells and confirm the potential role of TRPM3 ion channels in the aetiology and pathomechanism of CFS/ME.
Highlights
Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells
A recent investigation characterising Transient Receptor Potential Melastatin 3 (TRPM3) related responses in NK cells and B lymphocytes found a significant reduction in expression of TRPM3 on the NK cell surface in Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) patients compared with healthy controls (HC) (Nguyen et al, 2016)
This is consistent with our previous findings showing significantly reduced TRPM3 expression as well as significantly reduced intracellular Ca2+ mobilisation in isolated NK cells from CFS/ME patients compared with HC (Nguyen et al, 2017; Nguyen et al, 2016)
Summary
Chronic Fatigue Syndrome (CFS)/ Myalgic Encephalomyelitis (ME) is a debilitating disorder that is accompanied by reduced cytotoxic activity in natural killer (NK) cells. The objective of the present study was to characterise the TRPM3 ion channel function in NK cells from CFS/ME patients in comparison with healthy controls using whole cell patch-clamp techniques. A consistent feature of CFS/ ME in the literature is immune dysfunction, and more precisely a significant reduction in Natural Killer (NK) cell cytotoxicity, a hallmark of NK cell function (Brenu et al, 2012; Brenu et al, 2011; Curriu et al, 2013; Hardcastle et al, 2015; Huth et al, 2016a; Klimas et al, 1990; Maher et al, 2005; Natelson et al, 2002; Nijs & Frémont, 2008; Sharpe et al, 1991; Siegel et al, 2006; Stanietsky & Mandelboim, 2010)
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