Role of Cholinergic Anti-Inflammatory Pathway in Protecting Sepsis-Induced Acute Lung Injury through Regulation of the Conventional Dendritic Cells

Abstract

Background. The cholinergic anti-inflammatory pathway connects the immune response system and the nervous system via the vagus nerve. The key regulatory receptor is the α7-subtype of the nicotinic acetylcholine receptor (α7nAChR). Cholinergic anti-inflammatory pathway has been proved to be effective in suppressing the inflammation responses in acute lung injury (ALI). Dendritic cells (DCs), the important antigen-presenting cells, also express the α7nAChR. Past studies have indicated that reducing the quantity of mature conventional DCs and inhibiting the maturation of pulmonary DCs may prove effective for the treatment of ALI. However, the effects of cholinergic anti-inflammatory pathway on maturation, function, and quantity of DCs and conventional DCs in ALI remain unclear. Objective. It was hypothesized that cholinergic anti-inflammatory pathway may inhibit the inflammatory response of ALI by regulating maturation, phenotype, and quantity of DCs and conventional DCs. Methods. GTS-21 (GTS-21 dihydrochloride), an α7nAchR agonist, was prophylactically administered in sepsis-induced ALI mouse model and LPS-primed bone marrow-derived dendritic cells. The effects of GTS-21 were observed with respect to maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2 (type 2 conventional DCs) and the release of DC-related proinflammatory cytokines in vivo and in vitro. Results. The results of the present study revealed that GTS-21 treatment decreased the maturation of DCs and the production of DC-related proinflammatory cytokines in vitro and in sepsis-induced ALI mouse model; it reduced the quantity of CD11c+MHCII+ conventional DCs and CD11c+CD11b+ conventional DCs2 in vivo experiment. Conclusions. Cholinergic anti-inflammatory pathway contributes to the reduction in the inflammatory response in ALI by regulating maturation, phenotype, and quantity of DCs, conventional DCs, and conventional DCs2.

Vagus nerve SARS‐CoV‐2 infection and inflammatory reflex dysfunction: Is there a causal relationship?

“…If a fundamental mechanistic problem in the COVID‐19 cytokine storm is that the inflammatory reflex is impaired and there is a relative deficiency of acetylcholine to prevent inflammation, then it may be reasonable to consider administering cholinergic agents to restore the balance. In‐line with this reasoning, a systemic administration of the a7nAChR‐specific agonist GTS‐21 ameliorated experimental acute inflammatory lung injury by alleviating the accumulation of HMGB1 and neutrophils in the airways and in the circulation [63–65] (Fig. 5).…”

Advances in nanomaterial-targeted treatment of acute lung injury after burns

“…Inflammatory diseases of the lung are closely related to T-cell-mediated immune responses, and the main pathway is the processing of antigens by DCs, which act by presenting information to specific T cells [119]. L. Li [120] investigated the role of lung cDCs in the regulation of LPS-induced ALI (Fig.…”

α7- and α9-Containing Nicotinic Acetylcholine Receptors in the Functioning of Immune System and in Pain

“…Nicotine exposure to mouse and human DCs resulted in the increased expression of CD86 relative to CD80 and in the production of less IL-12, modulating the Th1/Th2 balance toward Th2 [ 138 ]. In a mouse model of sepsis-induced acute lung injury (ALI), GTS-21 reduced DC maturation and the production of pro-inflammatory cytokines, thereby reducing inflammatory responses in ALI [ 139 ].…”