Reg4 deficiency aggravates pancreatitis by increasing mitochondrial cell death and fibrosis

Area of Science:

• Gastroenterology
• Molecular Biology
• Regenerative Medicine

Background:

• The role of Regenerating gene family member 4 (Reg4) in pancreatitis pathogenesis is not fully understood.
• Investigating Reg4's mechanisms and therapeutic potential is crucial for pancreatitis treatment.

Purpose of the Study:

• To elucidate the contribution of Reg4 to pancreatitis pathogenesis.
• To evaluate the therapeutic effects of Reg4 in experimental pancreatitis models.

Main Methods:

• Reg4 deletion and recombinant Reg4 (rReg4) protein administration in experimental pancreatitis.
• Analysis of inflammatory infiltrates, mitochondrial cell death, autophagy, fibrosis, and cell proliferation.
• Investigation of the C-X-C motif ligand 12 (CXCL12)/C-X-C motif receptor 4 (CXCR4) axis and Reg4-exostosin-like glycosyltransferase 3 (Extl3) interaction.

Main Results:

• Reg4 deletion exacerbated acute pancreatitis by increasing inflammation and mitochondrial damage, and impairing autophagy recovery.
• In chronic pancreatitis, Reg4 deficiency worsened inflammation, fibrosis, and inhibited compensatory cell proliferation.
• Reg4 deficiency led to sustained CXCL12/CXCR4 axis activation, which was reversed by CXCR4 antagonist plerixafor (AMD3100).
• Reg4 potentially functions by binding to its receptor Extl3.

Conclusions:

• Reg4 exhibits therapeutic effects in pancreatitis, mitigating inflammation and fibrosis.
• Reg4 promotes cellular regeneration and improves recovery in experimental pancreatitis.
• Targeting the Reg4/CXCR4/Extl3 pathway may offer a novel therapeutic strategy for pancreatitis.