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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL070694-10
Application #
8467020
Study Section
Special Emphasis Panel (ZHL1-PPG-Y)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$263,626
Indirect Cost
$57,225
Name
University of Connecticut
Department
Type
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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
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
Garris, Christopher S; Wu, Linfeng; Acharya, Swati et al. (2013) Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol 14:1166-72
Xiong, Yuquan; Lee, Hyeuk Jong; Mariko, Boubacar et al. (2013) Sphingosine kinases are not required for inflammatory responses in macrophages. J Biol Chem 288:32563-73
Subramani, Jaganathan; Ghosh, Mallika; Rahman, M Mamunur et al. (2013) Tyrosine phosphorylation of CD13 regulates inflammatory cell-cell adhesion and monocyte trafficking. J Immunol 191:3905-12
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
Montrose, David C; Scherl, Ellen J; Bosworth, Brian P et al. (2013) S1P? localizes to the colonic vasculature in ulcerative colitis and maintains blood vessel integrity. J Lipid Res 54:843-51
Mendelson, Karen; Zygmunt, Tomasz; Torres-Vazquez, Jesus et al. (2013) Sphingosine 1-phosphate receptor signaling regulates proper embryonic vascular patterning. J Biol Chem 288:2143-56
Ghosh, Mallika; McAuliffe, Beata; Subramani, Jaganathan et al. (2012) CD13 regulates dendritic cell cross-presentation and T cell responses by inhibiting receptor-mediated antigen uptake. J Immunol 188:5489-99

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