Pancreas-specific ablation of beta1 integrin induces tissue degeneration by disrupting acinar cell polarity.
OBJECTIVE
Integrin contact with basement membrane is a major determinant of epithelial cell polarity. beta1 integrin heterodimers are the primary receptors for basement membrane in pancreatic acinar cells, which function to synthesize and directionally secrete digestive enzymes into a central lumen. Aberrant acinar secretion and exposure of the parenchyma to digestive enzyme activity lead to organ damage and pancreatitis.


METHODS
beta1 integrin conditional knockout mice were crossed to Ptf1a-Cre mice to ablate beta1 integrin in the pancreas. Histopathology of aged and cerulein-treated mice were assessed by histology and immunocytochemistry. Directional secretion was determined in vitro by FM1-43 loading with cerulein stimulation.


RESULTS
Pancreas-specific ablation of beta1 integrin led to progressive organ degeneration, associated with focal acinar cell necrosis and ductal metaplasia along with widespread inflammation and collagen deposition. beta1 Integrin-null pancreata were highly susceptible to cerulein-induced acute pancreatitis, displaying an enhanced level of damage with no loss in regeneration. Degenerating beta1 integrin-null pancreata were marked by disruption of acinar cell polarity. Protein kinase C epsilon, normally localized apically, was found in the cytoplasm where it can lead to intracellular digestive enzyme activation. beta1 Integrin-null acinar cells displayed indiscriminate secretion to all membrane surfaces, consistent with an observed loss of basolateral membrane localization of Munc18c, which normally prevents basal secretion of digestive enzymes.


CONCLUSIONS
Ablation of beta1 integrin induces organ atrophy by disrupting acinar cell polarity and exposing the pancreatic parenchyma to digestive enzymes.
Bombardelli
Lorenzo
L
Department of Pharmacology, Stony Brook University, Stony Brook, New York 11794-8651, USA.
Carpenter
Eileen S
ES
Wu
Alison P
AP
Alston
Ninche
N
DelGiorno
Kathleen E
KE
Crawford
Howard C
HC
D000367:Age Factors; D000681:Amylases / Q000097:blood; D000818:Animals; D016764:Cell Polarity; D002108:Ceruletide / Q000633:toxicity; D019012:Integrin beta1 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D046790:Pancreas, Exocrine / Q000473:pathology*; D051571:Protein Kinase C-alpha / Q000032:analysis; D051744:Protein Kinase C-epsilon / Q000032:analysis
D019012:Integrin beta1; D002108:Ceruletide; D051571:Protein Kinase C-alpha; D051744:Protein Kinase C-epsilon; D000681:Amylases