The CD13/aminopeptidase N cell surface peptidase is expressed on activated endothelial cells and normal cells of the myeloid lineage including monocytes, granulocytes, macrophages dendritic, and mast cells. We find that crosslinking of either monocytes or endothelial cells with activating monoclonal antibodies to CD13 significantly enhances cell-cell adhesion in a signal transduction dependent manner consistent with the antibody mimicking a natural CD13 activator that regulates cell adhesion. In agreement, while their hematopoietic profiles are normal, macrophages from CD13 null mice are significantly impaired in their ability to adhere to endothelial monolayers, suggesting CD13 participates in inflammatory monocyte/endothelial interactions. In addition, mice lacking CD13 are completely protected in a model of multiple sclerosis, strongly implicating a critical role in inflammatory autoimmune mechanisms as well. Investigation into the relevant molecular mechanisms showed that soluble recombinant CD13 blocks this adhesion, activated monocytes adhere to immobilized recombinant CD13 and both monocyte and endothelial cell CD13 are found in a single immunocomplex, suggesting that CD13 directly participates in the adhesion. Furthermore, adhesion is strictly dependent on sialyl moieties, implicating a role for the sialic acid binding proteins DSiglecsD in CD13 adhesion. To identify a physiologic source of the CD13 activator, serum from mice undergoing hypersensitivity reactions or atherosclerosis but not other inflammatory insults increases CDIS-dependent monocyte/endothelial adhesion, thus we can proteomically identify this intriguing CDIS-specific inflammatory regulator that dictates novel cell-cell interactions in response to specific challenges. Collectively, these data support a role for CD13 as a molecular interface that induces and participates in critical inflammatory cell interactions and may provide insights regarding the high levels of serum sialic acid associated with cardiovascular disease. The experimental plan will dissect the relative contribution of monocytic CD13 to inflammatory processes using conditional CD13 null animals in in vivo models of inflammation. In addition, we will identify the novel molecular mechanisms by which CD13

Public Health Relevance

Inflammation is linked to the progression of many human diseases such as cardiovascular disease, diabetes, rheumatoid arthritis, and cancer. In these diseases normally protective mechanisms become unbalanced and lead to tissue damage and intensification of disease. Understanding the molecules and mechanisms that regulate normal functions is critical to controlling their dysregulation in disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-PPG-Y)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
United States
Zip Code
Harel, Miriam; Ferrer, Fernando A; Shapiro, Linda H et al. (2016) Future directions in risk stratification and therapy for advanced pediatric genitourinary rhabdomyosarcoma. Urol Oncol 34:103-15
Gerber, Claire; Harel, Miriam; Lynch, Miranda L et al. (2016) Proximal tubule proteins are significantly elevated in bladder urine of patients with ureteropelvic junction obstruction and may represent novel biomarkers: A pilot study. J Pediatr Urol 12:120.e1-7
Blaho, Victoria A; Galvani, Sylvain; Engelbrecht, Eric et al. (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342-6
Ghosh, Mallika; Subramani, Jaganathan; Rahman, M Mamunur et al. (2015) CD13 restricts TLR4 endocytic signal transduction in inflammation. J Immunol 194:4466-76
Galvani, Sylvain; Sanson, Marie; Blaho, Victoria A et al. (2015) HDL-bound sphingosine 1-phosphate acts as a biased agonist for the endothelial cell receptor S1P1 to limit vascular inflammation. Sci Signal 8:ra79
Rahman, M Mamunur; Ghosh, Mallika; Subramani, Jaganathan et al. (2014) CD13 regulates anchorage and differentiation of the skeletal muscle satellite stem cell population in ischemic injury. Stem Cells 32:1564-77
Ghosh, Mallika; Gerber, Claire; Rahman, M Mamunur et al. (2014) Molecular mechanisms regulating CD13-mediated adhesion. Immunology 142:636-47
Blaho, Victoria A; Hla, Timothy (2014) An update on the biology of sphingosine 1-phosphate receptors. J Lipid Res 55:1596-608
Zhang, Yong; Tang, Wenwen; Zhang, Haifeng et al. (2013) A network of interactions enables CCM3 and STK24 to coordinate UNC13D-driven vesicle exocytosis in neutrophils. Dev Cell 27:215-26
Pereira, Flavia E; Cronin, Chunxia; Ghosh, Mallika et al. (2013) CD13 is essential for inflammatory trafficking and infarct healing following permanent coronary artery occlusion in mice. Cardiovasc Res 100:74-83

Showing the most recent 10 out of 89 publications