Abstract
CD93 is emerging as a novel regulator of inflammation; however, its molecular function is unknown. CD93 exists as a membrane-associated glycoprotein on the surface of cells involved in the inflammatory cascade, including endothelial and myeloid cells. A soluble form (sCD93) is detectable in blood and is elevated with inflammation. In this study, we demonstrate heightened susceptibility to thioglycollate-induced peritonitis in CD93(-/-) mice. CD93(-/-) mice showed a 1.6-1.8-fold increase in leukocyte infiltration during thioglycollate-induced peritonitis between 3 and 24 h that returned to wild type levels by 96 h. Impaired vascular integrity in CD93(-/-) mice during peritonitis was demonstrated using fluorescence multiphoton intravital microscopy; however, no differences in cytokine or chemokine levels were detected with Luminex Multiplex or ELISA analysis. C1q-hemolytic activity in CD93(-/-) mice was decreased by 22% at time zero and by 46% 3 h after thioglycollate injection, suggesting a defect in the classical complement pathway. Leukocyte recruitment and C1q-hemolytic activity was restored to wild type levels when CD93 was expressed on either hematopoietic cells or nonhematopoietic cells in bone marrow chimeric mice. However, elevated levels of sCD93 in inflammatory fluid were observed only when CD93 was expressed on nonhematopoietic cells. Because cell-associated CD93 was sufficient to restore a normal inflammatory response, these data suggest that cell-associated CD93, and not sCD93, regulates leukocyte recruitment and complement activation during murine peritonitis.
Highlights
CD93 is emerging as a novel regulator of inflammation; its molecular function is unknown
Leukocyte numbers in the peritoneal cavity were similar in wild type (WT) and CD932/2 mice prior to injection of thioglycollate ([0.54 6 0.11] 3 107 versus [0.60 6 0.13] 3 107, respectively); increased leukocyte recruitment into the peritoneal cavity was observed at 3 and 6 h after injection of thioglycollate in CD932/2 mice compared with WT controls (1.5- and 1.8-fold, respectively; p, 0.0001; Fig. 1A)
The total number of neutrophils and monocytes in the peritoneal cavity of CD932/2 mice was greater than WT (Fig. 2B, 2C), the relative percentage of each cell type was similar in WT and
Summary
CD93 is emerging as a novel regulator of inflammation; its molecular function is unknown. CD932/2 mice showed a 1.6–1.8-fold increase in leukocyte infiltration during thioglycollate-induced peritonitis between 3 and 24 h that returned to wild type levels by 96 h. Leukocyte recruitment and C1q-hemolytic activity was restored to wild type levels when CD93 was expressed on either hematopoietic cells or nonhematopoietic cells in bone marrow chimeric mice. Because cell-associated CD93 was sufficient to restore a normal inflammatory response, these data suggest that cell-associated CD93, and not sCD93, regulates leukocyte recruitment and complement activation during murine peritonitis. CD93 is expressed on a variety of cells involved in the inflammatory cascade, including neutrophils, monocytes, and endothelial cells. Abbreviations used in this article: BMDM, bone marrow-derived macrophage; CTLD, C-type lectin-like domain; EA, erythrocytes opsonized with anti-sheep Abs; sCD93, soluble form of CD93; TM, thrombomodulin; WT, wild type
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