The Cholinergic Anti-Inflammatory Pathway Delays TLR-Induced Skin Allograft Rejection in Mice: Cholinergic Pathway Modulates Alloreactivity

Abstract

Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.

Antidiabetic Effect of Galantamine: Novel Effect for a Known Centrally Acting Drug

“…In the current study, galantamine induced a shift towards an anti-inflammatory phenotype, evidenced by the increase of adiponectin, and the decrease of the transcription factor NF-κB, the signature cytokine TNF-α [ 70 ], and visfatin, which were elevated in the diabetic animals. The ability of galantamine to abate TNF-α level in non-diabetic models [ 5 , 71 ] may be attributed to the stimulation of the cholinergic anti-inflammatory pathway via the activation of α7nAChR [ 37 , 72 , 73 ] and/or elevation of adiponectin [ 5 ]. Although no direct data are available to correlate galantamine with NF-κB, yet inhibition of TNF-α and visfatin can be one possible pathway for the reduction of NF-κB [ 74 ] and vice versa [ 75 , 76 ].…”

MiRNA-122 promotes ischemia-reperfusion injury after lung transplantation via the TLR signaling pathway

“…MiRNAs are known to promote primary graft dysfunction through several signal transduction pathways (27). For instance, the TLR signaling pathway contributes to the pathogenesis following organ transplantation (28,29). As molecules that play an important role in innate immunity and inflammatory responses, TLRs can initiate cellular innate immunity by identifying specific structures of pathogenic microorganisms.…”