2. Academic Validation
  3. ERN2/XBP1-AGR2 mediated endoplasmic reticulum stress increased neutrophilic asthma mucus secretion

ERN2/XBP1-AGR2 mediated endoplasmic reticulum stress increased neutrophilic asthma mucus secretion

  • Int Immunopharmacol. 2026 Feb 15:171:116133. doi: 10.1016/j.intimp.2025.116133.
Jing Yang 1,  Xiaofang Li 1,  Bei Ye 1,  Zhiyan Luo 2,  Huiting Huang 3,  Xiaoyun Peng 2,  Wujin Wen 2,  Gang Liao 2,  Huiqiu Liang 2,  Yong Jiang 4,  Shaofeng Zhan 5,  Qiong Liu 6,  Xiufang Huang 7
Affiliations

Affiliations

  • 1 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China; The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Centre of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou, China.
  • 2 Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China.
  • 3 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 4 Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine, Shenzhen, China. Electronic address: [email protected].
  • 5 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: [email protected].
  • 6 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Electronic address: [email protected].
  • 7 The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China; The First Clinical Medical School, Guangzhou University of Chinese Medicine, Guangzhou, China; Lingnan Medical Research Centre of Guangzhou University of Chinese Medicine, Guangzhou, China; Guangdong Provincial Clinical Research Academy of Chinese Medicine, Guangzhou, China; State Key Laboratory of Traditional Chinese Medicine, Guangzhou 510405, China. Electronic address: [email protected].
PMID: 41483622 DOI: 10.1016/j.intimp.2025.116133
Abstract

A major pathogenic mechanism of neutrophilic asthma (NA) may be the excessive secretion of mucus, which causes variable degrees of airflow obstruction. This study showed the critical role of endoplasmic reticulum stress response (ERS) in NA mucus hypersecretion. Multiple bioinformatics methods indicated that ERN2 and AGR2 were essential genes in ERS in NA and were found to be tightly related to XBP1 and MUC5AC. Then, the NA mouse model, ERS model in HBE135-E6E7 and lentivirus-infected HEK-293 T cells were constructed to verify the bioinformatics results. Airway mucus hypersecretion and the intensity of ERS were decreased by inhibiting ERN2 in vivo (4μ8C) and in vitro (lentivirus). Furthermore, 4μ8C could dramatically reduce the concentration of protein in BALF, the levels of inflammatory cytokines in serum or BALF, and the quantity of leukocytes, particularly neutrophils, in BALF. Meanwhile, 4μ8C and lentivirus suppressed the mRNA and protein expression of ERN2, XBP1, AGR2 and MUC5AC and inhibited connections between them. The interaction between ERN2 and AGR2 was confirmed by molecular dynamics simulation and Co-IP assays in vitro. Therefore, we speculated that the primary method to lessen airway mucus hypersecretion in NA was to suppress the ERN2/XBP1-AGR2 axis to attenuate ERS, which lowered MUC5AC secretion.

Keywords

Bioinformation analysis; ERN2/XBP1-AGR2 axis; Endoplasmic reticulum stress; Mucus secretion; Neutrophilic asthma.

Figures
Products