Phagocytosis of Apoptotic Cells by Macrophages From NOD Mice Is Reduced
- 1Diabetes Research Laboratory, Department of Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada
- 2Department of Medicine, BC Research Institute of Children and Women’s Health, University of British Columbia, Vancouver, British Columbia, Canada
Macrophages limit inflammatory responses by clearing apoptotic cells. Deficiencies in apoptotic cell phagocytosis have been linked to autoimmunity. In this study, we determined the efficiency with which macrophages from diabetes-prone NOD and diabetes-resistant NOR, Idd5, Balb/c, and C57BL/6 mice phagocytose apoptotic thymocytes and NIT-1 insulinoma cells. Peritoneal and bone marrow-derived macrophages from NOD mice engulfed fewer apoptotic thymocytes than macrophages from Balb/c mice (P < 0.05). Peritoneal macrophages from NOR and Idd5 NOD congenic mice were more proficient at engulfment than their NOD counterparts. Annexin V blockade diminished apoptotic thymocyte clearance and heat-labile serum factors augmented clearance. Binding of apoptotic thymocytes to NOD macrophages was also reduced, suggesting that the deficiency in phagocytosis may be partly attributable to a recognition defect. Peritoneal macrophages from female Balb/c and NOD mice were equally efficient in the engulfment of microspheres, suggesting that the phagocytic deficiency observed in NOD mice was specific for apoptotic cells. In summary, we have demonstrated a deficiency in phagocytic function of macrophages from NOD mice. Normal and diabetes-prone neonatal rodents have a wave of β-cell apoptosis coincident with the onset of target organ inflammation. A constitutive defect in the clearance of apoptotic β-cells may be contributory to the initiation of autoimmunity.
Address correspondence and reprint requests to Dr. Diane T. Finegood, Diabetes Research Laboratory, School of Kinesiology, Simon Fraser University, 8888 University Dr., Burnaby, British Columbia, V5A 1S6. E-mail:.
Received for publication 29 November 2001 and accepted in revised form 16 May 2002.
BMDM, bone marrow-derived macrophage; DC, dendritic cell; dp, diabetes prone; dr, diabetes resistant; H&E, hematoxylin and eosin; PS, phosphatidylserine.