>2009 Research Director (DR2) at INSERM (U698, team 4 www.u698.fr)
>1999 Cardiology Fellow (PATT, Univ. Hospital Bichat/Beaujon, Paris, FR)
Expertise and research field
>1998 Immunopathology and immunomodulation of atherosclerotic diseases
Clinical studies in patients (clinical evaluation, peripheral blood and tissue analysis)
Experimental studies in mice (survival surgery, immunointervention, tissue analysis)
>2004 Immunoregulation in atherothrombosis, rheumatoid arthitis and multiple sclerosis
Clinical studies in patients (clinical evaluation, diagnostic tools and prognostic studies)
Experimental studies in mice (pre-clinical and molecular evaluation of candidate drugs)
Degrees and diplomas
2006 Research Leading Habilitation (HDR, Faculté de Médecine, Paris V, FR)
« Role of CD31 in atherosclerosis physiopathology »
2002 First Class Researcher (CR1, INSERM, Paris FR)
« The immunopathology of vascular remodeling »
2000 Doctor in Science (Karolinska Institute, Stockholm, SE and Univ. Paris 7, FR)
« The immune response in atherosclerosis and acute coronary syndromes »
1997 Post-graduate Specialization in Cardiology (Catholic University, Rome, IT)
« Immune-inflammatory markers in patients with coronary artery disease »
1993 Doctor in Medicine and Surgery (Catholic University, Rome, IT)
1987 Baccalaureate in Sciences (“Filolao” High School, Crotone, IT)
2011 Advanced Flow cytometry and sorting (BD Biosciences, Erembodegem, Belgium)
2010 In silico drug screening (Paris 7 University), Paris, France
2006 Protein-protein interaction, advanced training (Paris 7 University), Paris, France
2005 Habilitation for animal experimentation, including vital surgery, Paris, France
2000 Echocardiography Inter-universitary Diploma, Creteil, France, 2000
Membership of learned societies, discussion groups
>2005 Board Editor for Arteriosclerosis Thrombosis and Vascular Biology
>2004 European Cardiology Society Working group “Pathogenesis of Atherosclerosis” (WG 23)
>2006 Guest Member of the EVGN Network (European FP6, leader A. Tedgui)
2002-2005 Research network “Progenitor endothelial cells from blood” (INSERM, leader M. Aiach)
>1999 Reviewer for: J Exp Med, Lancet, Circulation, Arteriosclerosis Thrombosis and Vascular Biology, Atherosclerosis
Patents and licensing
My research work focuses on the role of inflammation and immune responses in atherosclerosis and its complications. We have contributed to this research field by showing that systemic and local immune responses are typically detectable both in experimental mouse models of atherosclerosis 1, 2and in patients with coronary atherothrombosis 3. While humoral immune responses appear to be protective 4, we have consistently observed that T-cell responses play a pathogenic role in atherosclerosis and atherothrombosis 5-9. Various putative immune target antigens, mainly stress and oxidatively modified proteins, have been proposed as the key inflammatory triggers. However, these antigens are also detected in asymptomatic individuals. The only difference between asymptomatic and symptomatic patients is that the lymphocytes are abnormally activated in the latter. We therefore reasoned that the abnormal immuno-inflammatory vascular responses observed in atherosclerosis and atherothrombosis could be due to a defective immune tolerance within the circulation 10.
In the most recent years, I have focused my attention on CD31 (PECAM-1), a regulatory receptor that is expressed constitutively and exclusively by the cells of the blood-vessel interface (endothelial cells, platelets and blood leukocytes). CD31 consists of a single chain molecule comprising 6 Ig-like extracellular domains numbered starting from the most membrane-distal one. At the time of its cloning, this molecule was thought to belong to the adhesion molecule because of this structure structural. However, at variance with the other Ig-like glycoprotein family member, CD31 also has a long cytoplasmic tail containing two ImmunoTyrosine-based Inhibitory Motif (ITIM)s. A number of studies have subsequently shown that CD31 acts as other ITIM-bearing regulatory receptors 11.
Crosslinking of the membrane distal Ig-like domains of CD31 induces outside-in inhibitory signaling triggered by the phosphorylation of its ITIMs, and the recruitment and activation of SH2-containing phosphatases. The mechanical engagement of the distal CD31 domains is necessary for driving the redistribution of CD31 molecules at the cell membrane via the cis homo-oligomerization of domain 6 12. Due to its homophilic properties and inhibitory function, CD31 is unique in being able to exert a mutual regulatory function in interacting CD31+ cells, regardless of the cell type, in the circulation.
Interestingly, although the expression of CD31 is constitutive, a variable number of blood T cells are found to CD31 negative with age.
We therefore reasoned that the appearance of clinical manifestations of atherosclerotic diseases could concur with the loss of CD31 (and of its regulatory function) on peripheral T cells. This hypothesis has been evaluated in two studies: one in aged apoE KO mice 13and one in patients with abdominal atherothrombotic aortic aneurysm 14. Both studies showed that the percentage of T cells lacking surface CD31, assessed by multiparameter flow-cytometry in the peripheral blood, is reduced in individuals with most severe atherothrombotic disease.
We found that lesion-infiltrated T cells are mainly CD31 negative and that T-cell activation is easier and exaggerated in the absence of CD31 13, 14 suggesting that the lack of CD31 regulation could facilitate the abnormal immune responses that are linked to atherothrombosis. On the contrary, overexpression of CD31 is able to prevent the development of atherosclerotic plaques and stabilize their phenotype by reducing the extent of intraplaque neovascularization and hemorrhage in apoE Ko mice 15.
We have demonstrated that CD31 is lost by an extracellular cleavage and shedding of the molecule 16 from activated T cells, macrophages, dendritic cells and platelets. Interestingly, the CD31 inhibitory pathway can be recovered in all these cells with a homophilic peptide. We are therefore developing a therapeutic use of this peptide for atherothrombosis and other chronic inflammatory diseases.
1. Caligiuri G, Nicoletti A, Zhou X, Tornberg I, Hansson GK. Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice. Atherosclerosis. 1999; 145(2): 301-8.
2. Nicoletti A, Kaveri S, Caligiuri G, Bariety J, Hansson GK. Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. The Journal of clinical investigation. 1998; 102(5): 910-8.
3. Caligiuri G, Liuzzo G, Biasucci LM, Maseri A. Immune system activation follows inflammation in unstable angina: pathogenetic implications. Journal of the American College of Cardiology. 1998; 32(5): 1295-304.
4. Caligiuri G, Nicoletti A, Poirier B, Hansson GK. Protective immunity against atherosclerosis carried by B cells of hypercholesterolemic mice. The Journal of clinical investigation. 2002; 109(6): 745-53.
5. Caligiuri G, Paulsson G, Nicoletti A, Maseri A, Hansson GK. Evidence for antigen-driven T-cell response in unstable angina. Circulation. 2000; 102(10): 1114-9.
6. Nicoletti A, Paulsson G, Caligiuri G, Zhou X, Hansson GK. Induction of neonatal tolerance to oxidized lipoprotein reduces atherosclerosis in ApoE knockout mice. Molecular medicine (Cambridge, Mass. 2000; 6(4): 283-90.
7. Caligiuri G, Liuzzo G, Biasucci LM, Maseri A. Immune system activation follows inflammation in unstable angina: pathogenetic implications. Journal of the American College of Cardiology. 1998; 32(5): 1295-304.
8. Khallou-Laschet J, Caligiuri G, Groyer E, Tupin E, Gaston AT, Poirier B, et al. The proatherogenic role of T cells requires cell division and is dependent on the stage of the disease. Arteriosclerosis, thrombosis, and vascular biology. 2006; 26(2): 353-8.
9. Caligiuri G, Rudling M, Ollivier V, Jacob MP, Michel JB, Hansson GK, et al. Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Molecular medicine (Cambridge, Mass. 2003; 9(1-2): 10-7.
10. Caligiuri G, Nicoletti A. Lymphocyte responses in acute coronary syndromes: lack of regulation spawns deviant behaviour. European heart journal. 2006; 27(21): 2485-6.
11. Newman PJ, Newman DK. Signal transduction pathways mediated by PECAM-1: new roles for an old molecule in platelet and vascular cell biology. Arteriosclerosis, thrombosis, and vascular biology. 2003; 23(6): 953-64.
12. Newton JP, Buckley CD, Jones EY, Simmons DL. Residues on both faces of the first immunoglobulin fold contribute to homophilic binding sites of PECAM-1/CD31. The Journal of biological chemistry. 1997; 272(33): 20555-63.
13. Caligiuri G, Groyer E, Khallou-Laschet J, Al Haj Zen A, Sainz J, Urbain D, et al. Reduced immunoregulatory CD31+ T cells in the blood of atherosclerotic mice with plaque thrombosis. Arteriosclerosis, thrombosis, and vascular biology. 2005; 25(8): 1659-64.
14. Caligiuri G, Rossignol P, Julia P, Groyer E, Mouradian D, Urbain D, et al. Reduced immunoregulatory CD31+ T cells in patients with atherosclerotic abdominal aortic aneurysm. Arteriosclerosis, thrombosis, and vascular biology. 2006; 26(3): 618-23.
15. Groyer E, Nicoletti A, Ait-Oufella H, Khallou-Laschet J, Varthaman A, Gaston AT, et al. Atheroprotective effect of CD31 receptor globulin through enrichment of circulating regulatory T-cells. Journal of the American College of Cardiology. 2007; 50(4): 344-50.
16. Fornasa G, Groyer E, Clement M, Dimitrov J, Compain C, Gaston AT, et al. TCR Stimulation Drives Cleavage and Shedding of the ITIM Receptor CD31. J Immunol. 2010; 184: in press (PMID: 20400708).