TY - JOUR
T1 - Cholinergic stimulation of the immune system protects against lethal infection by Salmonella enterica serovar Typhimurium
AU - Fernandez-Cabezudo, Maria J.
AU - Lorke, Dietrich E.
AU - Azimullah, Sheikh
AU - Mechkarska, Milena
AU - Hasan, Mohammed Y.
AU - Petroianu, Georg A.
AU - Al-Ramadi, Basel K.
PY - 2010/7
Y1 - 2010/7
N2 - The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.
AB - The cholinergic nervous system has been demonstrated to attenuate the inflammatory response during sepsis via the inhibitory action of acetylcholine (ACh) on macrophages. These findings were largely based on experimental sepsis models using endotoxin as the inducing agent. Herein, however, we report that the specific inhibition of acetylcholinesterase (AChE) renders animals more resistant to infection by a virulent strain of Salmonella enterica serovar Typhimurium, a Gram-negative enteric pathogen. Inhibition of AChE was induced by a subchronic exposure to paraoxon, a potent anti-cholinesterase metabolite of the organophosphorous compound parathion. Our findings indicate that inhibition of AChE enhanced survival of infected mice in a dose-dependent fashion and this correlated with efficient control of bacterial proliferation in target organs. Immunologically, inhibition of AChE enabled the animals to mount a more effective inflammatory anti-microbial response, and to secrete higher levels of interleukin-12, a key T helper type 1-promoting cytokine. The ACh-induced enhancement in resistance to infection was abrogated by co-administration of an oxime which can reactivate AChE. Hence, in a model of Gram-negative bacterial infection, cholinergic stimulation is shown to enhance the anti-microbial immune response leading to effective control of bacterial proliferation and enhanced animal survival.
KW - Acetylcholine
KW - Cholinergic anti-inflammatory pathway
KW - Innate immunity
KW - Organophosphate
KW - Salmonella infection
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U2 - 10.1111/j.1365-2567.2009.03238.x
DO - 10.1111/j.1365-2567.2009.03238.x
M3 - Article
C2 - 20408892
AN - SCOPUS:77953510237
SN - 0019-2805
VL - 130
SP - 388
EP - 398
JO - Immunology
JF - Immunology
IS - 3
ER -