ErbB4 promotes M2 activation of macrophages in idiopathic pulmonary fibrosis
Yu Jiang1, Jialin Shi1, Junhao Zhou2
1School of Medicine, Shaoxing University, Shaoxing 312000, Zhejiang, China.
Abstract:
Idiopathic pulmonary fibrosis (IPF) is the most common and fatal diffuse fibrotic lung disease accompanied by macrophage M2 activation. ErbB4 is involved in and affects the process of inflammation. In this study, we determined that the mRNA level and protein expression of ErbB4 and M2 cytokine members were increased in the serum of IPF patients. In mouse alveolar macrophage MH-S cells, after knocking down ErbB4 by siRNA, the mRNA level and protein expression of M2 activator induced by interleukin (IL)-4 were decreased compared with the control group. Activating by ErbB4 agonist neuromodulatory protein (NRG)-1, IL-4-induced M2 program was promoted. Mechanistically, treated with NRG-1 in MH-S cells, the phosphorylation level of Akt did not change, while the phosphorylation level of ERK increased. Using SCH772984 to inhibit ERK pathway, the increasing IL-4-induced M2 activation by NRG-1 was inhibited, and the high level of M2 activator protein expression and mRNA expression was restored. Collectively, our data support that ErbB4 and M2 programs are implicated in IPF, and ErbB4 participates in the regulation of M2 activation induced by IL-4 through the ERK pathway.
Insights
ErbB4 signaling promotes M2 macrophage activation in idiopathic pulmonary fibrosis (IPF). This pathway, involving ERK signaling, offers a potential therapeutic target for IPF, a fatal lung disease.
Area of Science:
- Immunology
- Pulmonary Medicine
- Cell Biology
Background:
- Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by M2 macrophage activation.
- ErbB4 plays a role in inflammatory processes.
Purpose of the Study:
- To investigate the role of ErbB4 in M2 macrophage activation in IPF.
- To elucidate the signaling pathway through which ErbB4 influences M2 activation.
Main Methods:
- Measured ErbB4 and M2 cytokine levels in IPF patients' serum.
- Utilized siRNA to knockdown ErbB4 in MH-S cells.
- Administered ErbB4 agonist (NRG-1) and ERK inhibitor (SCH772984).
- Assessed M2 activation markers and signaling pathway phosphorylation (Akt, ERK).
Main Results:
- ErbB4 and M2 cytokine levels were elevated in IPF patients.
- ErbB4 knockdown reduced IL-4-induced M2 activation.
- NRG-1 treatment promoted M2 activation via ERK phosphorylation, not Akt.
- ERK inhibition reversed NRG-1-mediated M2 activation.
Conclusions:
- ErbB4 is implicated in IPF pathogenesis.
- ErbB4 regulates IL-4-induced M2 macrophage activation through the ERK pathway.
- Targeting ErbB4-ERK signaling may be a therapeutic strategy for IPF.
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