Abstract
Ryanodine receptors (RyRs), the intracellular Ca2+ release channels, are expressed in T lymphocytes and other types of immune cells. Modulation of RyRs has been shown to affect T cell functions in vitro and immune responses in vivo. The effects of modulation of RyRs on the development of autoimmune diseases have not been investigated. Here we studied how modulation of RyRs through administration of RyR inhibitor dantrolene or introducing a gain-of-function RYR1-p.R163C mutation affects clinical progression of experimental autoimmune encephalomyelitis (EAE) in mice, a T cell-mediated autoimmune neuroinflammatory disease. We found that daily intraperitoneal administration of 5 or 10 mg/kg dantrolene beginning at the time of EAE induction significantly reduced the severity of EAE clinical symptoms and dampened inflammation in the spinal cord. The protective effect of dantrolene on EAE was reversible. Dantrolene administration elicited dose-dependent skeletal muscle weakness: mice that received 10 mg/kg dose developed a waddling gait, while 5 mg/kg dantrolene dose administration produced a reduction in four-limb holding impulse values. Mice bearing the gain-of-function RYR1-p.R163C mutation developed the EAE clinical symptoms faster and more severely than wild-type mice. This study demonstrates that RyRs play a significant role in EAE pathogenesis and suggests that inhibition of RyRs with low doses of dantrolene may have a protective effect against autoimmunity and inflammation in humans.
Highlights
Ryanodine receptors (RyRs) are a family of intracellular Ca2+ release channels located in the membranes of the smooth endoplasmic reticulum
To confirm the involvement of RyRs in EAE pathogenesis, we studied the impact of RyRs: type 1 (RyR1) gain-of-function mutation on EAE progression using the R163C HET mice
EAE is an established animal model of T cell-mediated autoimmune disease, which recapitulates many features of neuroinflammation and axonal damage observed in Multiple sclerosis (MS) in humans (Constantinescu et al, 2011; Glatigny and Bettelli, 2018; Lassmann, 2020; Martinez and Peplow, 2020)
Summary
Ryanodine receptors (RyRs) are a family of intracellular Ca2+ release channels located in the membranes of the smooth endoplasmic reticulum. Three different genes encode RyRs: type 1 (RyR1), type 2 (RyR2), and type 3 (RyR3) with additional transcripts produced by alternative splicing (Fill and Copello, 2002). The role of RyRs in immune cell Ca2+ signaling is best understood in T lymphocytes, in which RyRs regulate Ca2+ release from the intracellular store and, subsequently, store-operated Ca2+ entry (Dadsetan et al, 2008; Thakur et al, 2012; Fomina, 2021). The expression of different types of RyRs depends on the environmental factors and functional state of T cells. Cytokines and T cell receptor agonists induce expression of RyR1 and RyR2, of which the former appears to be a predominant isoform in activated T cells (Hosoi et al, 2001; Thakur et al, 2012)
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