Deficiency of Mesencephalic Astrocyte-Derived Neurotrophic Factor Aggravates Acute Pancreatitis in Mice.

Acute pancreatitis (AP) is a common, potentially severe inflammatory disease of the pancreas. Although environmental triggers such as alcohol and gallstones are well known, only a subset of exposed individuals develop AP, suggesting that genetic or intrinsic factors contribute to disease onset and severity. Endoplasmic reticulum (ER) stress has emerged as a key pathogenic mechanism in AP due to the essential role of the ER in protein synthesis, folding, and degradation (proteostasis). Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an ER stress-inducible protein highly expressed in the pancreas and critical for proteostasis, but its role in AP remains unclear. To investigate this, pancreas-specific Manf knockout mice were generated using the Cre/loxP system and subjected them to caerulein- or alcohol-induced AP. In both models, MANF deficiency worsened pancreatic injury, as evidenced by elevated ER stress markers [phosphorylated eukaryotic initiation factor 2 alpha (p-eIF2α) and glucose-regulated protein 78 (GRP78)], apoptosis (cleaved caspase-3), inflammation (IL-6 and tumor necrosis factor α), regeneration (Ki67), and elevated pancreatic lipase levels. In the caerulein model, male Manf knockout mice exhibited higher oxidative stress and macrophage infiltration than female mice. In the alcohol model, both sexes showed increased inflammation and macrophage infiltration, but oxidative stress and high mobility group box 1 expression were again more prominent in male mice. These findings suggest that MANF contributes to pancreatic resilience under stress conditions and may influence sex-dependent responses during AP.