Hemin-activated macrophages home to the pancreas and protect from acute pancreatitis via heme oxygenase-1 induction
Ikuo Nakamichi, … , Eugene C. Butcher, M. Bishr Omary
Ikuo Nakamichi, … , Eugene C. Butcher, M. Bishr Omary
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3007-3014. https://doi.org/10.1172/JCI24912.
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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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Figure 4

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Effect of hemin on in vivo macrophage homing to the pancreas using biolu...
Effect of hemin on in vivo macrophage homing to the pancreas using bioluminescence imaging. (A) Experimental scheme of cell transfer. Hemin was injected 3 times i.p. (arrows) into luciferase-overexpressing (luciferase+/+) mice, then peritoneal cells were harvested and macrophages were selected using anti–Mac-1 magnetic beads. Luciferase/Mac-1 double-positive cells were transferred i.p. to wild-type (luciferase–/–) mice that were preinjected with 1 dose of hemin or vehicle 24 hours prior to the transfer. This hemin injection was necessary to induce pancreatic chemokines (Figure 3F). (B–D) Live images of recipient intact anesthesized mice were taken 5 minutes (B) or 24 hours (C) after cell transfer. Livers and pancreata were removed 24 hours after the transfer, followed by imaging (D). The signal intensity scale bar is shown below each image. (E–G) A duplicate of the pancreata shown in part D (from recipients receiving donor cells from hemin-injected animals) was double stained with antibodies to luciferase (E) and F4/80 (F). Similar double staining of pancreata from recipient animals receiving donor cells from V-injected mice showed background staining (e.g., E [inset] for the anti-luciferase staining). (G) A merged image of the double stain. Scale bar: 50 μm.