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Developmental endothelial locus-1: Seine Effekte auf die Adhäsion von hämatopoietischen Zellen

 

The leukocyte adhesion cascade is an important paradigm of immunity and mediates leukocyte recruitment in acute or chronic inflammatory responses. Leukocyte recruitment requires several adhesive interactions between leukocytes and endothelial cells. The adhesion of leukocytes to the endothelial cell surface is mediated by interactions between leukocyte integrins, such as the beta1-integrin family member VLA-4 (a4b1) or the beta2-integrin family members LFA-1 (aLb2, CD11a/CD18), Mac-1 (aMb2, CD11b/CD18, complement receptor-3), and their endothelial counter-receptors of the immunoglobulin superfamily (ICAM-1, VCAM-1) (1). Our lab has made significant contributions to the leukocyte adhesion cascade, including the recent identification of a novel endogenous inhibitor of leukocyte recruitment, the endothelial-derived molecule Developmental Endothelial Locus-1 (Del-1, Edil3) (2-4).

Mobilization of hematopoietic stem cells (HSC) from the bone marrow to the periphery takes place upon infection. HSC mobilization is important for bone marrow transplantation and can be stimulated by GCSF- or GMCSF. Moreover, the success of bone marrow transplantation requires the engraftment of HSC to the bone marrow of the recipient (5). HSC mobilization and engraftment are dependent on adhesive interactions between HSC and the bone marrow endothelium. Integrin adhesion receptors, such as LFA-1 or VLA-4 and their counter-receptors ICAM-1 and VCAM-1, respectively, or chemokines, such as SDF-1 and its receptor CXCR4, contribute to HSC engraftment, as well as to HSC mobilization (6). HSC mobilization requires the de-adhesion of HSC from the stem cell niche and their reverse migration through the endothelium of the bone marrow. For example, GCSF induces proteolytic enzymes like matrix metalloproteases, elastase or cathepsin G that cleave chemokines, such as SDF-1 or disturb VLA-4-dependent adhesive interactions in the bone marrow, thereby promoting HSC mobilization (7,8).

In the present project we aim at understanding the mechanisms underlying the inhibitory function of Del-1 on integrin-dependent hematopoietic cell adhesion and the function of Del-1 in HSC mobilization. We hypothesize that Del-1 may promote HSC retention in the bone marrow or that Del-1 inhibits mobilization of HSC from the bone marrow.

References:

1)   Ley K, Laudanna C, Cybulsky MI, Nourshargh S (2007): Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 7, 678-89

 

2)   Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, Orlandi A, Kundu RK, Zheng YY, Prieto DR, Ballantyne CM, Constant SL, Aird W, Papayannopoulou T, Gahmberg CG, Udey MC, Vajkoczy P, Quertermous T, Dimmeler S, Weber C, Chavakis T (2008): Del-1 is an endogenous inhibitor of leukocyte-endothelial adhesion limiting inflammatory cell recruitment. Science. 322, 1101-4

 

3)   Orlova V, Choi EY, Xie C, Chavakis E, Bierhaus A, Ihanus E, Ballantyne C, Gahmberg C, Bianchi M, Nawroth P, Chavakis T (2007): A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J. 26, 1129-39

 

4)   Choi EY, Orlova VV, Fagerholm S, Numri S, Zhang L, Ballantyne CM, Gahmberg CG, Chavakis T (2008): Cbl-b deficiency activates LFA-1-dependent inflammatory cell recruitment by stimulating the interaction cytoplasmic tail of the LFA-1 beta-chain and 14-3-3 proteins. Blood 111, 3607-14

 

5)   Kopp HG, Avecilla ST, Hooper AT, Rafii S (2005): The Bone Marrow Vascular Niche: Home of HSC Differentiation and Mobilization. Physiology 20, 349–356

 

6)   Chavakis E, Aicher A, Heeschen C, Sasaki K, Kaiser R, El Makhfi N, Urbich C, Peters T, Scharffetter-Kochanek K, Zeiher AM, Chavakis T and Dimmeler S (2005): Role of beta2-integrins for homing and neovascularization capacity of endothelial progenitor cells. J Exp Med 201, 63-72

 

7)   McQuibban GA, Butler GS, Gong JH, Bendall L, Power C, Clark-Lewis I, and Overall CM (2001): Matrix metalloproteinase activity inactivates the CXC chemokine stromal cell-derived factor-1. J Biol Chem 276, 43503–43508

 

8)   Papayannopoulou T (2000): Mechanisms of stem-/progenitor-cell mobilization: the anti-VLA-4 paradigm. Semin Hematol. 37,11-8

 

 

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Funding program:

DFG