β2-Adrenergic Receptor Enhances the Alternatively Activated Macrophages and Promotes Biliary Injuries Caused by Helminth Infection

Abstract

The autonomic nervous system has been studied for its involvement in the control of macrophages; however, the mechanisms underlying the interaction between the adrenergic receptors and alternatively activated macrophages (M2) remain obscure. Using FVB wild-type and beta 2 adrenergic receptors knockout, we found that β2-AR deficiency alleviates hepatobiliary damage in mice infected with C. sinensis. Moreover, β2-AR-deficient mice decrease the activation and infiltration of M2 macrophages and decrease the production of type 2 cytokines, which are associated with a significant decrease in liver fibrosis in infected mice. Our in vitro results on bone marrow–derived macrophages revealed that macrophages from Adrb2−/− mice significantly decrease M2 markers and the phosphorylation of ERK/mTORC1 induced by IL-4 compared to that observed in M2 macrophages from Adrb2+/+. This study provides a better understanding of the mechanisms by which the β2-AR enhances type 2 immune response through the ERK/mTORC1 signaling pathway in macrophages and their role in liver fibrosis.

Molecular Mechanisms of Clonorchis sinensis-Host Interactions and Implications for Vaccine Development

“…These authors also showed that infection of mice resulted in mixed M1 and alternatively activated macrophages (M2) ( Kim et al, 2017a ). The percentage of M1 and M2 macrophages were different according to the stage of the infection with the increase in M1 macrophages in the early stage of infection, while the M2 macrophages were predominant in the late stage of the infection especially in the fibrotic part ( Kim et al, 2017a ; Koda et al, 2021 ). Besides, the various components of C. sinensis induces the differentiation of macrophages to both M1 and M2 macrophages ( Wi et al, 2012 ; Kim et al, 2017a ; Yan et al, 2020a ; Kang et al, 2020 ; Koda et al, 2021 ).…”

“…The percentage of M1 and M2 macrophages were different according to the stage of the infection with the increase in M1 macrophages in the early stage of infection, while the M2 macrophages were predominant in the late stage of the infection especially in the fibrotic part ( Kim et al, 2017a ; Koda et al, 2021 ). Besides, the various components of C. sinensis induces the differentiation of macrophages to both M1 and M2 macrophages ( Wi et al, 2012 ; Kim et al, 2017a ; Yan et al, 2020a ; Kang et al, 2020 ; Koda et al, 2021 ). Moreover, it has been shown that macrophages are associated with the resistance of mice to the second infection by C. sinesis , which showed the decrease of IL-10 and IL-13 produced by M2 macrophages and increases of specific IgE, IgG1, and IgG2a levels in serum at 1 week or 4 weeks following re-infection ( Kim et al, 2017b ).…”

“…The autonomic nervous system has been studied for its involvement in the control of macrophages activation in recent years ( Lorton and Bellinger, 2015 ; Stakenborg et al, 2020 ). The role of beta 2 adrenergic receptors (β2-AR, a kind of guanine nucleotide-binding G protein–coupled receptor that can bind with norepinephrine and epinephrine to induce diverse physiological effects) have also been shown to regulate the activation of M2 macrophages during C. sinensis infection in our recent study ( Koda et al, 2021 ). It was showed that deletion of Adrb2 (encoding β2-AR) was associated with a decrease in liver fibrosis and the decrease in the infiltration of M2 macrophages in C. sinensis infected mice ( Koda et al, 2021 ).…”

“…The role of beta 2 adrenergic receptors (β2-AR, a kind of guanine nucleotide-binding G protein–coupled receptor that can bind with norepinephrine and epinephrine to induce diverse physiological effects) have also been shown to regulate the activation of M2 macrophages during C. sinensis infection in our recent study ( Koda et al, 2021 ). It was showed that deletion of Adrb2 (encoding β2-AR) was associated with a decrease in liver fibrosis and the decrease in the infiltration of M2 macrophages in C. sinensis infected mice ( Koda et al, 2021 ). Moreover, the in vitro study showed that β2-AR promoted M2 activation mediated by mTORC1 since inhibition of mTORC1 by rapamycin significantly decreased M2 markers in macrophages isolated from β2-AR defective mice ( Koda et al, 2021 ).…”

“…It was showed that deletion of Adrb2 (encoding β2-AR) was associated with a decrease in liver fibrosis and the decrease in the infiltration of M2 macrophages in C. sinensis infected mice ( Koda et al, 2021 ). Moreover, the in vitro study showed that β2-AR promoted M2 activation mediated by mTORC1 since inhibition of mTORC1 by rapamycin significantly decreased M2 markers in macrophages isolated from β2-AR defective mice ( Koda et al, 2021 ).…”