Vagus Nerve through 7 nAChR Modulates Lung Infection and Inflammation: Models, Cells, and Signals
Modulatory effects of CAP on different cell populations.
Sepsis; CLP; acid-induced ALI; pneumonia
nAChR agonists, VNS, and genetic depletion
(i) nAChR is expressed on the surface of human and mouse alveolar macrophages. (ii) Cholinergic agonists inhibit TNF- production and HMGB1 release from macrophages. (iii) Vagus nerve stimulation does not inhibit TNF production in -subunit-deficient mice. (iv) Increased cytokine production in -subunit-deficient mice during endotoxaemia. (v) Nicotinic treatment prevents lethal endotoxemia. (vi) Deficiency of nAChR increases BAL proinflammatory cytokines.
(i) GTS-21 attenuated TNF production in monocytes stimulated with peptidoglycan, polyinosinic-polycytidylic acid, CpG, HMGB1, and RAGE-modified albumin. (ii) GTS-21 decreased TNF levels in endotoxin-stimulated whole blood obtained from patients with severe sepsis. (iii) Nicotine inhibited the actions of AGE-2 and AGE-3. Nonselective and selective nAChR antagonists, mecamylamine and -bungarotoxin, reversed the inhibitory effects of nicotine, suggesting the involvement of nAChR stimulation.
(i) nAChR is expressed on the surface of neutrophils. (ii) Administration of nicotine, a pharmacologic agonist of the cholinergic anti-inflammatory pathway, significantly reduces levels of CD11b, a -integrin involved in cell adhesion and leukocyte chemotaxis, on the surface of neutrophils in a dose-dependent manner and this function requires the spleen. (iii) Vagus nerve stimulation significantly attenuates neutrophil surface CD11b levels only in the presence of an intact and innervated spleen. (iv) nAChR+Gr1+ neutrophils are increased in the lungs and activation of nAChR reduces neutrophil transalveolar migration in E. coli pneumonia. (v) Activation of nAChR decreases proinflammatory cytokine production in neutrophils.
Reduction of neutrophils in the lung renders protective effects on sepsis and ALI
(i) Under lipopolysaccharide LPS stimulation, TNF-α produced by splenic MNCs was 117% higher in LCR sham and 52% higher in LCR surgery compared with HCR sham and surgery rats. (ii) LPS-stimulated TNF- production could not be inhibited by an α7 nAChR agonist LCR rat MNCs, whereas inhibition by the adrenergic agonist, salmeterol, was significantly less (−35%) than that obtained in HCR rats.
Rats with the metabolic syndrome have ineffective CAP
(i) Nicotine upregulated the expression of nAChR by activating PI3K-Akt pathway in murine DCs. (ii) Nicotine stimulation could enhance DCs’ ability of HBV-specific T cell proliferation and IL-12 secretion. (iii) Adoptive transfer of nicotine stimulated DCs could induce HBV-specific CTL priming in vivo and those CTL had cytolytic activities. (iv) Nicotine had equal efficiencies to 2 ng/mL IFN-γ in DCs-mediated T cell proliferation.
nAChR genetic depletion; bone marrow transplantation
(i) CD4+ T cell population that is stimulated by norepinephrine to release ACh. (ii) ChAT+ B cells release ACh after stimulation with sulfated cholecystokinin. (iii) -Adrenoreceptors of regulatory lymphocytes are essential for vagal neuromodulation of the innate immune system. (iv) Cholinergic lymphocytes reestablish splenic protection and the potential of cholinergic agonists to rescue immunocompromised animals from established sepsis. (v) Increased DSS-induced inflammation was associated with reduced CD4+CD25+Foxp3+ regulatory T cell numbers in recipients. Adoptive transfer of CD4+ T cells from vagotomized animals (but not CD4+ T cells from sham-operated controls) to naive DSS-treated recipients resulted in increased inflammatory scores.
T and B lymphocytes synthesize ACh, regulating neutrophil recruitment and innate immunity
nAChR agonist: nicotine, genetic depletion of nAChR
(i) Human type II alveolar epithelial cells express nAChR. (ii) Nicotine activates and upregulates nicotinic acetylcholine receptors in bronchial epithelial cells. (iii) Human epithelial HEp-2 cells express nAChR. Treatment of HEp-2 cells with nicotine after infection with bacteria resulted in a significant increase in C. pneumoniae inclusion numbers in cells. (iv) nAchR activation by topical agonist application or deletion of the nAChR antagonist catestatin reduced antimicrobial peptide (AMP) activity in skin extracts and increased susceptibility to methicillin-resistant Staphylococcus aureus and group A Streptococcus infections. (v) nAChR is in fundamental cellular processes relevant to lung development, injury and repair, and carcinogenesis
In the lung epithelial cells, involvement of nAChR in controlling bacteria growth, cell growth, and repair
(i) HuMVECs express the cell surface nAChR. (ii) ACh and nAChR agonists inhibit TNF-induced adhesion molecule expression by HuMVECs. (iii) ACh and nAChR agonists reduce TNF-induced chemokine production by endothelial cells. (iv) Changes in molecular (upregulation, affinity, and conformational states) and cellular (distribution, association with membranes) properties of the 7AChR related to angiogenesis (wound-repair cell migration) and atherogenesis (alterations in cholesterol content) were studied in living endothelial cells. (v) The nAChRs on endothelial cells modulate key angiogenic processes, including endothelial cell survival, proliferation, and migration.
Endothelial cell activation and leukocyte binding; angiogenesis; atherogenesis
nAChR Cre, Rosa26-Flox, YFP labeling; bone marrow transplantation
(i) In the adult, on average 20–25% of the total CD45+ myeloid and lymphoid cells of the bone marrow (BM), blood, spleen, lymph nodes, and Peyer’s patches are nAChR+lin+. (ii) This hematopoietic nAChR+lin+ subpopulation is also found in Sca1+cKit+ BM cells. (iii) Both nAChR+lin+ and nAChR+lin− BM cells can reconstitute the immune system of naïve irradiated recipient mice. (iv) Functionally the nAChR+lin+ and nAChR+lin−lineages differ in response to LPS challenge. (v) Production of IL-12/23(p40) was enhanced in the α7 nAChR+lin+ cells in response to LPS challenge.
nAChR-expressing HSCs could repopulate during inflammation
(i) MSCs also expressed nAChR. (ii) Stimulation of MSCs with the nicotinic receptor agonist nicotine and the muscarinic receptor agonist muscarine induced immediate and transient increases in intracellular Ca2+ concentration. (iii) At nontoxic concentrations, nicotine increased spontaneous migration of hMSCs, whereas chemotaxis of hMSCs toward C3a and bFGF in vitro and migration of intravenously infusion hMSCs into bone marrow and spleen in vivo were inhibited. (iv) The antagonist for the alpha 7 homopolymer, bungarotoxin, blocked the inhibitory effect of nicotine on chemotactic factor-induced migration of hMSCs.
(i) EPCs expressed nAChR. (ii) Incubation with nicotine enhanced viable, migratory, adhesive, and in vitro vasculogenesis capacity of late EPCs. (iii) The effect of nicotine on late EPCs can be attenuated by mecamylamine or -bungarotoxin. (iv) Nicotine treatment increased the number of EPCs in the bone marrow and spleen and increased their incorporation into the vasculature of ischemic tissue. Administration of nicotine increased markers of EPC mobilization.
(i) Fibroblasts from synovial tissue of arthritis patients expressed nAChR. (ii) In nAChR knockout mice, a significant increase in the incidence and severity of arthritis and increased synovial inflammation and joint destruction were seen.