Vagal tonic activity modulates immune suppression in sepsis survivors
JOURNAL OF IMMUNOLOGY(2018)
摘要
Abstract Sepsis survivors exhibit persistent immune dysfunction and compromised quality of life with premature mortality due to increased vulnerability to infections. Previously we demonstrated in a cecal ligation and puncture (CLP) model, sepsis survivors had a reduced TNFα response to LPS-challenge in vivo. The vagus nerve is known to modulate TNFα production. To evaluate the role of the vagus nerve in the diminished TNFα production, sepsis-surviving mice were subjected to bilateral subdiaphragmatic vagotomy 2 weeks post-CLP. CLP-surviving vagotomized mice exhibit increased (p<0.05) TNFα levels in response to LPS-challenge 4 weeks post surgery compared to CLP. Moreover, vagus nerve stimulation in sham mice dampened (p<0.05) the LPS-induced TNFα response while it had no effect in CLP-surviving mice; suggesting that vagus nerve signaling is constitutively active in CLP-sepsis survivors. To identify whether there was an alteration in the number of acetylcholine-producing T cells that relay the vagus signal to splenic macrophages, we used ChAT-EGFP mice. Our findings show that the frequency of splenic ChAT-EGFP+ cells among memory CD4+CD44highCD62LlowT cells is increased (p<0.001) in CLP-surviving mice compared to sham, and vagotomy in these mice resulted in decreased (p<0.01) frequency of ChAT-EGFP+ cells, buttressing the conclusion that the vagus nerve is constitutively firing action potentials to activate more ChAT+ T cells. Methyllycaconitine, the α7 nicotinic acetylcholine receptor antagonist, increased (p<0.01) LPS-induced TNFα secretion in CLP-surviving mice compared to saline treated-CLP. In summary, our study demonstrates that altered vagus nerve activity contributes to the immune impairment in sepsis survivors.
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