Norbert Leitinger

Education

  • PhD, University of Vienna

Primary Appointment

  • Associate Professor, Pharmacology

Contact

Research Interest(s)

Role of lipid oxidation products in inflammation and vascular immunology in atherosclerosis and diabetes

Research Description

Research Interests: Role of lipid oxidation products in inflammation and vascular immunology in atherosclerosis and diabetes. 1. Resolution of acute and propagation of chronic inflammation. 2. Mechanisms of endothelial-monocyte interaction in chronic inflammation. 3. Intracellular signaling induced by oxidized lipids. 4. Pattern recognition in innate immunity (Toll like receptors). 5. Antiinflammatory activities of PPARs. 6. Regulation of heme oxygenase-1.

Techniques in Use: Quantitative RT-PCR, Promoter-reporter assays, Gel shift, siRNA, Transfection, HPLC and ESI-MS, TLC, Cell culture, Immunohistochemistry, Flow cytometry, SDS-PAGE, Western blotting, Mouse models of inflammation.

Current Summary: Inflammation is generally accompanied by tissue damage associated with oxidation of host macromolecules by inflammation-derived free radicals. Recent evidence suggests that phospholipid oxidation products (OxPL), which are generated by oxidation of cellular membranes, lipoproteins and during apoptosis, represent danger signals that modulate inflammation and the activation of the innate immune response. My laboratory has recently demonstrated that certain OxPL are potent negative feedback regulators of innate immune responses via blocking the interaction of endotoxin with its Toll-like receptor-4 (TLR-4). Ongoing projects aim to 1) identify mechanisms by which OxPL modulate a specific immune response and delineate pathways that determine the signal differentiation between OxPL (altered self) and pathogen-associated molecular patterns (PAMPs) such as LPS (non-self), 2) investigate how acute inflammation is resolved or driven into a chronic state by OxPL, and 3) examine how monocyte specificity is brought about in chronic inflammation. The long-term goals of this research are to understand how oxidative modification of lipids during tissue damage leads to an inadequate immune response during infection, causes disruption of the tightly controlled balance of immune tolerance, and ultimately provokes chronic inflammation.

Peroxisomal proliferator activated receptors (PPARs) are ligand-activated transcription factors belonging to the superfamily of nuclear hormone receptors. In addition to regulating the fatty acid and glucose metabolism in liver, myocardium and adipose tissue, they have been shown to exert direct anti-inflammatory effects in the vascular wall, although the underlying mechanisms are poorly understood. Consequently PPAR ligands are able to slow down the progression of inflammatory vascular diseases like atherosclerosis and restenosis. Currently, we investigate the hypothesis that the induction of the potent anti-inflammatory gene heme oxygenase-1 (HO-1) by PPARs in the vascular wall significantly contributes to their anti-inflammatory effects.

Selected Publications

  • Halterman J, Kwon H, Leitinger N, Wamhoff B. NFAT5 expression in bone marrow-derived cells enhances atherosclerosis and drives macrophage migration. Frontiers in physiology. 2012;3 313. PMID: 22934063 | PMCID: PMC3429083
  • Lohman A, Weaver J, Billaud M, Sandilos J, Griffiths R, Straub A, Penuela S, Leitinger N, Laird D, Bayliss D, Isakson B. S-nitrosylation inhibits pannexin 1 channel function. The Journal of biological chemistry. 2012;287(47): 39602-12. PMID: 23033481 | PMCID: PMC3501028
  • Meher A, Sharma P, Lira V, Yamamoto M, Kensler T, Yan Z, Leitinger N. Nrf2 deficiency in myeloid cells is not sufficient to protect mice from high-fat diet-induced adipose tissue inflammation and insulin resistance. Free radical biology & medicine. 2012;52(9): 1708-15. PMID: 22370093 | PMCID: PMC3383807
  • Adamson S, Leitinger N. Phenotypic modulation of macrophages in response to plaque lipids. Current opinion in lipidology. 2011;22(5): 335-42. PMID: 21841486 | PMCID: PMC3979355
  • Kadl A, Sharma P, Chen W, Agrawal R, Meher A, Rudraiah S, Grubbs N, Sharma R, Leitinger N. Oxidized phospholipid-induced inflammation is mediated by Toll-like receptor 2. Free radical biology & medicine. 2011;51(10): 1903-9. PMID: 21925592 | PMCID: PMC3197756
  • Manichaikul A, Wang Q, Shi Y, Zhang Z, Leitinger N, Shi W. Characterization of Ath29, a major mouse atherosclerosis susceptibility locus, and identification of Rcn2 as a novel regulator of cytokine expression. American journal of physiology. Heart and circulatory physiology. 2011;301(3): H1056-61. PMID: 21666121 | PMCID: PMC3191074
  • Rao J, DiGiandomenico A, Artamonov M, Leitinger N, Amin A, Goldberg J. Host derived inflammatory phospholipids regulate rahU (PA0122) gene, protein, and biofilm formation in Pseudomonas aeruginosa. Cellular immunology. 2011;270(2): 95-102. PMID: 21679933 | PMCID: PMC3415270
  • Rao J, Elliott M, Leitinger N, Jensen R, Goldberg J, Amin A. RahU: an inducible and functionally pleiotropic protein in Pseudomonas aeruginosa modulates innate immunity and inflammation in host cells. Cellular immunology. 2011;270(2): 103-13. PMID: 21704311 | PMCID: PMC3432393
  • Heberlein K, Straub A, Best A, Greyson M, Looft-Wilson R, Sharma P, Meher A, Leitinger N, Isakson B. Plasminogen activator inhibitor-1 regulates myoendothelial junction formation. Circulation research. 2010;106(6): 1092-102. PMID: 20133900 | PMCID: PMC2848897
  • Sharma R, Sharma P, Kim Y, Leitinger N, Lee J, Fu S, Ju S. IL-2-controlled expression of multiple T cell trafficking genes and Th2 cytokines in the regulatory T cell-deficient scurfy mice: implication to multiorgan inflammation and control of skin and lung inflammation. Journal of immunology (Baltimore, Md. : 1950). 2010;186(2): 1268-78. PMID: 21169543 | PMCID: PMC3136806
  • "Obese" smooth muscle cells fail to assemble collagen fibrils. Circulation research. 2009;104(7): 826-8. PMID: 19359604
  • Cherepanova O, Pidkovka N, Sarmento O, Yoshida T, Gan Q, Adiguzel E, Bendeck M, Berliner J, Leitinger N, Owens G. Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration. Circulation research. 2009;104(5): 609-18. PMID: 19168440 | PMCID: PMC2758767
  • Johnstone S, Ross J, Rizzo M, Straub A, Lampe P, Leitinger N, Isakson B. Oxidized phospholipid species promote in vivo differential cx43 phosphorylation and vascular smooth muscle cell proliferation. The American journal of pathology. 2009;175(2): 916-24. PMID: 19608875 | PMCID: PMC2716985
  • Kadl A, Galkina E, Leitinger N. Induction of CCR2-dependent macrophage accumulation by oxidized phospholipids in the air-pouch model of inflammation. Arthritis and rheumatism. 2009;60(5): 1362-71. PMID: 19404946 | PMCID: PMC2745196
  • Wright M, Kim J, Hock T, Leitinger N, Freeman B, Agarwal A. Human haem oxygenase-1 induction by nitro-linoleic acid is mediated by cAMP, AP-1 and E-box response element interactions. The Biochemical journal. 2009;422(2): 353-61. PMID: 19534727 | PMCID: PMC2881470