Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients.

Stanley Du Preez,Sonya Marshall-Gradisnik,Helene Cabanas,Natalie Eaton-Fitch,Donald Staines

doi:10.3390/ijerph182211879

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.

Highlights

Natural killer (NK) cells are granular lymphocytes that provide anti-viral and antitumor defense primarily as part of the innate immune response
No significant differences in age, gender, and body mass index (BMI) were identified between groups (Table 1)
All included participants were within the reference ranges for each full blood count (FBC) parameter and there were no significant differences between groups for these parameters

Summary

Introduction

Natural killer (NK) cells are granular lymphocytes that provide anti-viral and antitumor defense primarily as part of the innate immune response. The two major human NK cell subsets include cluster of differentiation (CD)56bright CD16dim/- and CD56dim CD16+. Immunosurveillance and elimination of transformed autologous cells through cytotoxic effector mechanisms are principally performed by CD56dim CD16+ NK cells circulating in peripheral blood [2,3,4]. NK cell cytotoxicity is mediated by the degranulation of cytotoxic effector molecules including perforin, granzyme, and death ligands stored within secretory lysosomes [5,6,7,8,9]. Interleukin-2 (IL-2) stimulation significantly enhances the reactivity of NK cells with target cells via a mechanism termed lymphokineactivated killing (LAK) [10,11,12,13].

Methods

Results

Discussion

Conclusion