Description
This study provides new information on the anti-inflammatory effects of Acetylcholine and the role that cholinergic lymphocytes cells may play in regulating inflammation in the pulmonary system during influenza infection. Acetylcholine (ACh) is classically characterized by its neuronal origins and significant roles in the central and peripheral nervous system. Recent discoveries indicate that the cholinergic system functions in other cell types and tissues, including a number of immune cells and airway epithelial cells – both now known to be major sources of non-neuronal ACh. ACh is known to play a major role in regulating inflammation and tissue remodeling during inflammatory lung diseases, and in vivo studies of acute inflammation, such as following influenza infection, have shown that ACh can induce anti-inflammatory effects via the 7-nicotinic acetylcholine receptors (nAChR) expressed on many cell types. Influenza A Virus (IAV) infected ChAT promoter-GFP transgenic mice treated with the potent choline re-uptake inhibitor, Hemicholinium-3 (HC3), showed an impaired ability to recover weight lost during infection as well as a significant increase in mortality when compared to vehicle control counterparts. Expression of the Ionized calcium binding adaptor molecule 1 (Iba1)/ Allograft Inflammatory Factor-1 (AIF-1), known to have pro- inflammatory properties, were found to be significantly higher in the lungs of influenza infected animals treated with HC3 than those of influenza infected vehicle control animals. While it is unclear whether these effects are due to the inhibition of ACh released by infiltrating cholinergic lymphocytes or other ACh sources, cholinergic mechanisms have proven paramount in host survival after infection.This study demonstrates that 1) subsets of CD4+ and CD8+ T Cells entering the airways of influenza-infected mice actively produce ACh, potentially acting on the nAChR to play a role in mechanisms responsible for initiating or assisting tissue repair, 2) treatment with a cholinergic antagonist (HC3) results in lung tissues remaining in a significant pro- inflammatory state, and 3) treatment with a cholinergic antagonist (HC3) greatly impairs recovery from influenza infection and ultimately increases mortality. Together, these findings clearly demonstrate that the cholinergic system is critical for host recovery and survival from influenza infection in the mouse model.
