TY - JOUR
T1 - Cholinergic stimulation prevents the development of autoimmune diabetes
T2 - Evidence for the modulation of Th17 effector cells via an IFNγ-dependent mechanism
AU - George, Junu A.
AU - Bashir, Ghada
AU - Qureshi, Mohammed M.
AU - Mohamed, Yassir A.
AU - Azzi, Jamil
AU - Al-Ramadi, Basel K.
AU - Fernández-Cabezudo, Maria J.
N1 - Funding Information:
We wish to thank Mr. Saeed Tariq for his invaluable assistance with the confocal microscopy. We also like to thank Prof. Eric Mensah-Brown for his advice on the STZ murine model and Ms. Amna Al-Zaabi and Mr Sheikh Azimullah for their initial work on this project. This work was funded by a grant from the Scientific Research Council, UAE University, United Arab Emirates (NRF-21M074) and by Sheikh Hamdan Medical Research Grants Award, United Arab Emirates (MRG-22/2011-2012) to MF-C.
Publisher Copyright:
© 2016 George, Bashir, Qureshi, Mohamed, Azzi, al-Ramadi and Fernández-Cabezudo.
PY - 2016/10/13
Y1 - 2016/10/13
N2 - Type I diabetes (T1D) results from T cell-mediated damage of pancreatic β-cells and loss of insulin production. The cholinergic anti-inflammatory pathway represents a physiological link connecting the central nervous and immune systems via vagus nerve, and functions to control the release of proinflammatory cytokines. Using the multiple low-dose streptozotocin (MLD-STZ) model to induce experimental autoimmune diabetes, we investigated the potential of regulating the development of hyperglycemia through administration of paraoxon, a highly specific acetylcholinesterase inhibitor (AChEI). We demonstrate that pretreatment with paraoxon prevented hyperglycemia in STZ-treated C57BL/6 mice. This correlated with a reduction in T cell infiltration into pancreatic islets and preservation of the structure and functionality of β-cells. Gene expression analysis of pancreatic tissue revealed that increased peripheral cholinergic activity prevented STZ-mediated loss of insulin production, this being associated with a reduction in IL-1β, IL-6, and IL-17 proinflammatory cytokines. Intracellular cytokine analysis in splenic T cells demonstrated that inhibition of AChE led to a shift in STZ-induced immune response from a predominantly disease-causing IL-17-expressing Th17 cells to IFNγ-positive Th1 cells. Consistent with this conclusion, inhibition of AChE failed to prevent STZ-induced hyperglycemia in IFNγ-deficient mice. Our results provide mechanistic evidence for the prevention of murine T1D by inhibition of AChE and suggest a promising strategy for modulating disease severity.
AB - Type I diabetes (T1D) results from T cell-mediated damage of pancreatic β-cells and loss of insulin production. The cholinergic anti-inflammatory pathway represents a physiological link connecting the central nervous and immune systems via vagus nerve, and functions to control the release of proinflammatory cytokines. Using the multiple low-dose streptozotocin (MLD-STZ) model to induce experimental autoimmune diabetes, we investigated the potential of regulating the development of hyperglycemia through administration of paraoxon, a highly specific acetylcholinesterase inhibitor (AChEI). We demonstrate that pretreatment with paraoxon prevented hyperglycemia in STZ-treated C57BL/6 mice. This correlated with a reduction in T cell infiltration into pancreatic islets and preservation of the structure and functionality of β-cells. Gene expression analysis of pancreatic tissue revealed that increased peripheral cholinergic activity prevented STZ-mediated loss of insulin production, this being associated with a reduction in IL-1β, IL-6, and IL-17 proinflammatory cytokines. Intracellular cytokine analysis in splenic T cells demonstrated that inhibition of AChE led to a shift in STZ-induced immune response from a predominantly disease-causing IL-17-expressing Th17 cells to IFNγ-positive Th1 cells. Consistent with this conclusion, inhibition of AChE failed to prevent STZ-induced hyperglycemia in IFNγ-deficient mice. Our results provide mechanistic evidence for the prevention of murine T1D by inhibition of AChE and suggest a promising strategy for modulating disease severity.
KW - Acetylcholine
KW - IFNγ
KW - Inhibition of AChE
KW - Neuroimmunology
KW - Th17
KW - Type I diabetes
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U2 - 10.3389/fimmu.2016.00419
DO - 10.3389/fimmu.2016.00419
M3 - Article
AN - SCOPUS:84997354361
VL - 7
JO - Frontiers in Immunology
JF - Frontiers in Immunology
SN - 1664-3224
IS - OCT
M1 - 419
ER -