ALI is characterized by inflammatory cell infiltration and recruitment to the injured lung interstitium. Among them, DCs are the APCs that play a significant role in inflammatory response in the case of sepsis-induced lung injury. Numerous studies have suggested that by adopting different ways to decrease recruitment of activated DCs and cDCs in the lung may reduce the incidences of lung injury [7, 8]. In our present study, it was found that GTS-21 treatment regulated the maturation of DCs and the release of DC-related pro-inflammatory cytokines in vitro and in sepsis-induced mice model, and reduced the quantity of CD11c+MHCII+ cDCs and CD11c+CD11b+ cDCs2 in vivo experiment. Thus, it can be inferred that the activation of CAP may cause decreased inflammatory response in ALI through the regulation of maturation, phenotype, and quantity of DCs, cDCs, and cDCs2.
The acute inflammatory response in ALI not only includes the activation of innate and adaptive immune but also certain specific activities of the autonomic nervous system. The vagus nerve is considered to perform anti-inflammatory functions, by inhibiting the release of pro-inflammatory cytokines and protecting the lung from pathological injury; this anti-inflammatory function of the vagus nerve is termed as CAP [15]. It has been confirmed that CAP protects the lungs from infection and sepsis. In this signaling pathway, α7nAChR is a key target receptor that can attenuate the production of pro-inflammatory mediators from inflammatory cells, such as macrophages and DCs, at the same time as expressing itself on the surface of these inflammatory cells [6, 16]. A number of studies have shown that the activation of CAP inhibited differentiation and maturation of DCs, reduced DC-associated cytokine release and ameliorated the inflammatory responses in the body [6, 17]. However, the relationship between CAP and DCs in ALI remains unclear. In studies conducted by the investigators, it was found that the anti-inflammatory effect of the CAP agonist GTS-21 on DCs in sepsis-induced ALI: GTS-21 significantly inhibited the expression of MHCII, CD40, and CD86 on the surface of DCs and also the release of DC-related pro-inflammatory cytokines (IL-6, TNF-α, IL-18, IL-1β, IL-12p40, and HMGB1).
DCs through identification of the antigens of the pathogens, present antigens to activate T cells and initiate antigen-specific cellular immune responses, which are associated with many diseases, and play a critical role in the pathological process of ALI. In mouse and human beings, there are different types of DCs with different phenotypes, functions, and localizations that form an immune system, which is distributed across all organs of the body and is responsible for immune-surveillance [18–21]. DCs can be classified into two main lineages: cDCs and pDCs, which are crucial for the priming phase of the immune response. A number of studies have reported that marked increase in mature cDCs plays a key pro-inflammatory role in lung injury. As ALI progresses, cDCs express MHCII and CD80, which are rapidly accumulated in the lung interstitium, resulting in the production of a range of inflammatory mediators [7, 8, 21, 22]. These findings are consistent with the findings of the current study. Moreover, the data obtained in the current study also confirmed that immuno-modulatory effects of CAP on cDCs in pathological process of ALI using GTS-21. GTS-21 caused significant reduction in the quantity of CD11c+MHCII+ cDCs in LPS-induced mice model and in in vitro experiment. The data suggested that the anti-inflammatory activity of the CAP in ALI can be attributed to regulation of the number and accumulation of cDCs.
cDCs can also be further divided into two main subsets: cDCs1 and cDCs2. In mouse, the cDCs1 are characterized by the expression of CD103, and cDCs2 phenotype being CD11c+MHCII+CD11b+. The subset cDCs1 perform a specialized function of recognizing exogenous antigens and activating the CD8+ T cell immune response, whereas the other subset cDCs2 is primarily responsible for presenting endogenous antigens to CD4+ T cells and stimulating the polarization in these cells [23–25]. CD11c+CD11b+ cDCs are the most abundant DCs in the lymphoid organs and are also found in the spleen, skin, and lung tissues. Previous studies have demonstrated that CD11c+CD11b+ cDCs2 derived Th (T help cell) 17, Th2-immune responses in asthma, lung emphysema, and COPD [26–28]. CD11c+CD11b+ cDCs2 also produce pro-inflammatory cytokines such as IL-6 and IL-23 [28, 29]. Li et al. [30] reported that when CD11c+CD11b+ cDCs2 were co-cultured with T cells or LPS, they not only displayed immuno-regulatory characteristics but also played a crucial role in the induction of immune tolerance of experimental autoimmune encephalomyelitis (EAE). However, the role of CD11c+CD11b+ cDCs2 in ALI remains unclear, in particular, the relationship between cDCs2 and CAP. In the current study, the number of CD11c+CD11b+ cDCs2 in the spleen and lung were found be upregulated in the LPS-induced ALI mice. In addition, the results also demonstrated that GTS-21, the CAP agonist downregulated the phenotypic expression of cDCs2 in ALI mice model.