Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction
Ikuo Nakamichi, Aida Habtezion, Bihui Zhong, Christopher H. Contag, Eugene C. Butcher, M. Bishr Omary
Ikuo Nakamichi, Aida Habtezion, Bihui Zhong, Christopher H. Contag, Eugene C. Butcher, M. Bishr Omary
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Research Article Cell biology

Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction

Abstract

Hemin upregulates heme oxygenase-1 (HO-1), a stress-induced enzyme implicated in protection from a variety of injuries while its related isoform HO-2 is constitutively expressed. The role of hemin or HO-1 in the pancreas and their potential modulation of pancreatic injury are unknown. We show that HO-1 is induced in pancreatitis caused by caerulein and more prominently in severe pancreatitis caused by feeding a choline-deficient diet (CDD). Intraperitoneal hemin administration dramatically increases peritoneal and pancreas macrophages that overexpress HO-1 in association with pancreatic induction of the chemoattractants monocyte chemotactic protein-1 and macrophage inflammatory protein-1α but not RANTES or macrophage inflammatory protein-2. Hemin administration before CDD feeding protected 8 of 8 mice from lethality while 7 of 16 controls died. Protection is mediated by HO-1–overexpressing macrophages since hemin-primed macrophages home to the pancreas after transfer to naive mice and protect from CDD-induced pancreatitis. Suppression of hemin-primed peritoneal cell HO-1 using HO-1–specific small interfering RNA prior to cell transfer abolishes protection from CDD-induced pancreatitis. Similarly, hemin pretreatment in caerulein-induced pancreatitis reduces serum amylase and lipase, decreases pancreatic trypsin generation, and protects from lung injury. Therefore, hemin-like compounds or hemin-activated macrophages may offer novel therapeutic approaches for preventing acute pancreatitis and its pulmonary complication via upregulation of HO-1.

Authors

Ikuo Nakamichi, Aida Habtezion, Bihui Zhong, Christopher H. Contag, Eugene C. Butcher, M. Bishr Omary

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Effect of hemin or pancreatic injury on HO-1 induction and inhibition of...
Effect of hemin or pancreatic injury on HO-1 induction and inhibition of pancreatic injury by hemin. (A and B) Total tissue homogenates were obtained from pancreata of caerulein-injected (cae-injected) or CDD-fed mice. Two age- and sex-matched mice were used for each time point. Homogenates were tested by blotting, using antibodies to HO-1 or HO-2. (C) Mice (3 mice/condition) were given hemin (H) by i.p. injection (4 times during 1 week or 8 times during 2 weeks). Two control (Co) mice were injected with vehicle alone. Pancreatic homogenates were then obtained and blotted with anti–HO-1 and anti–HO-2. (D–G) Mice were injected with saline (S), hemin, or vehicle (V) (8 mice/group) 3 times (arrows) followed by feeding with CDD for 3 days, then harvesting of the pancreata. HO-1 and HO-2 were analyzed by blotting of pancreatic homogenates (3 mice/group). The number of mice that died in each cohort of 8 mice is shown, and the survival difference was significant (P < 0.03) when comparing controls (saline and vehicle) with hemin-injected mice. Representative H&E stainings of pancreata from mice that survived CDD feeding are shown. Scale bar: 50 μm. Note the marked pancreas edema (ED) and necrosis (N) in the saline- (not shown) and vehicle-injected mice as compared with the hemin group.