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Tanya Mayadas, PhD
Senior Scientist, Brigham and Women's Hospital

Brigham and Women's Hospital
Department of Pathology
75 Francis Street
Boston, MA 02115

Research Location: Harvard New Research Building

Phone: 617-525-4336
Research Email: tmayadas@rics.bwh.harvard.edu,

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Research Narrative:

Our laboratory is interested in understanding mechanisms of inflammation focusing both on the molecular basis of neutrophil recruitment, activation and function in autoimmune mediated diseases, and the endothelial dependent pathways regulating vascular permeability to macromolecules.

 

An inflammatory response requires the recruitment of innate immune cells (e.g. neutrophils and monocytes) through their interaction with the endothelium, followed by the induction of processes that allow them to engulf targets, release proteinases and generate reactive oxygen species to eliminate the offending stimuli. This innate immune response is critical for host defense but also contributes to tissue injury associated with inflammatory diseases. A major interest of the laboratory is to elucidate the neutrophil dependent mechanisms of tissue injury in autoimmune diseases such as glomerulonephritis, and the contribution of adhesion receptors and associated signaling pathways in regulating the activation and function of this cell type.  Related to our interest in glomerulonephritis, which is a leading cause of renal failure worldwide, we aim to understand the role of two TNF receptors, TNFR1 and TNFR2 on the endothelium, in the pathogenesis of IgG immune complex mediated glomerulonephritis.

 

In addition to our interest in leukocyte biology, our research has a strong vascular biology focus. Vascular permeability permits the passage of small molecules required for maintaining tissue fluid homeostasis. An increase in permeability is a hallmark of inflammation, and hyperpermeability and loss of endothelial barrier function is associated with many diseases from acute respiratory distress syndrome to diabetes and cancer. We study mechanisms of cAMP dependent regulation of endothelial cell junction remodeling, a dynamic process that controls vascular integrity, permeability and cell migration. We aim to determine how cAMP induced activation of Epac1, a cAMP responsive guanine exchange factor for Rap GTPases markedly increases basal endothelial barrier function and counteracts leakage induced by permeability inducing agents. In particular, we focus on delineating the role of Epac1, Rap GTPases, A-kinase anchoring protein-9 (AKAP9) and microtubule dynamics in this process.

 

Research Projects

·         Delineate how two opsonic receptors on neutrophils, the β2 (CD18) integrin Mac-1 (complement C3 receptor) and the FcγRs (receptors for IgG), coordinate neutrophil recruitment and cytotoxic functions in the context of IgG mediated autoimmune diseases and infection.

·         Identify the molecular determinants of leukocyte recruitment and target organ injury in IgG-immune complex mediated glomerulonephritis and lupus nephritis.

·         Elucidate cAMP dependent signaling mechanisms that regulate endothelial junctional remodeling.

 

Our research primarily exploits a) in vitro molecular biological and biochemical approaches and functional assays in primary human and murine neutrophils and endothelial cells, and b) in vivo models of disease and time lapse intravital microscopy in genetically engineered mice developed by our lab and others

 

Some highlights of our research are: i) generated a Mac-1 knock-out, and uncovered a novel method of neutrophil apoptosis triggered by this receptor that involved complement C3-mediated phagocytosis and NADPH oxidase mediated oxidative burst followed by caspase 8 activation, ii) demonstrated the central importance of neutrophil human FcγRs in acute and chronic glomerulonephritis using novel transgenic animals generated in the lab, iii) identified a new role for neutrophil FcγRs in the recruitment of neutrophils to immune complexes deposited within the vasculature using intravital microscopy, and assigned context-specific roles for the uniquely human neutrophil FcγRIIA and FcγRIIIB in this process, iv) determined how Mac-1 and FcγRs relay intracellular signals to achieve desired effector functions in the context of antibody- and complement-mediated inflammation, v) demonstrated a modulatory role for Mac-1 in the development of lupus nephritis, using a new humanized model of lupus nephritis developed in the lab, vi) elucidated an essential role for TNFR2 and downstream signaling in the pathogenesis of antibody-induced proliferative glomerulonephritis, vii) demonstrated that Epac1 activation of Rap GTPases markedly increased basal endothelial barrier function and counteracted leakage induced by thrombin through downregulation of Rho GTPases.

 

Keywords: Inflammation; autoimmune disease; neutrophils; endothelial cells; leukocyte recruitment; IgG immune complexes; complement C3; Mac-1; FcγRs; TNF receptors; cAMP; permeability; Epac1; genetically engineered mice; innate immunity

 

Publications:

 

Selected peer-reviewed publications

1.     Coxon A, Barkalow FJ, Askari S, Rieu P, Sharpe AH, von-Andrian UH, Arnaout MA, Mayadas TN. A novel role for the β2 integrin, CD11b/CD18, in neutrophil apoptosis:  A homeostatic mechanism in inflammation. Immunity 1996; 5:653-666

 

2.     Tang TT, Rosenkranz A, Assmann KJM, Goodman MJ, Gutierrez-Ramos J-C, Carroll MC, Cotran RS, Mayadas TN. A role for Mac-1 (CD11b/CD18) in Fc?R interactions in vivo:  Mac-1 deficiency abrogates sustained neutrophil adhesion and proteinuria in Fc-dependent anti-glomerular basement membrane nephritis. J. Exp. Med: 1997; 186:1853-1863.

 

3.     Rosenkranz AR, Mendrick DL, Cotran RS, Mayadas TN.  P-selectin deficiency exacerbates experimental glomerulonephritis:  A protective role for endothelial P-selectin in inflammation. J. Clin. Invest: 1999; 103:649-659.

 

4.     Coxon AC, Tang TT, Mayadas TN. Cytokine activated endothelial cells delay neutrophil apoptosis both in vitro and in vivo: a role for endothelial derived granulocyte-macrophage colony stimulating factor. J. Exp. Med: 1999; 190:923-34.

 

5.     Coxon A, Cullere X, Knight S, Sethi S, Wakelin MW, Luscinskas FW, Mayadas TN. FcγRIII mediates neutrophil recruitment to immune complexes: A mechanism for neutrophil accumulation in immune-mediated inflammation. Immunity 2001; 14:693-704.

 

6.     Sethi S, Ziouzenkova O, Ni H, Wagner DD, Plutzky J, Mayadas TN. Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPARα. Blood 2002; 100:1340-6.

 

7.     Zhang B, Hirahashi J, Cullere X, Mayadas TN. Determinants of phagocytosis induced cell death in neutrophils: Cross-talk between caspase 8, oxygen radicals and MAPK/ERK activation. J. Biol. Chem. 2003; 278:28443-54.

 

8.     Martinez Gakidis A, Cullere X, Olson T, Wilsbacher JL, Zhang B, Moores Sl, Ley K, Swat W, Mayadas T, Brugge JS. 2004. Vav GEFs are required for ?2 integrin-dependent functions of neutrophils. J. Cell Biol. 2004; 166:273-282.

 

9.     Stokol T, Xiao L, Knight S, Stavrakis G, Botto M, von Andrian UH, Mayadas TN. Complement C1q governs deposition of circulating immune complexes and leukocyte FcγRs mediate subsequent neutrophil recruitment. J. Exp. Med. 2004;  200:835-46

 

10.  Cullere X, Shaw SK, Andersson L, Hirahashi J, Luscinskas FW, Mayadas TN. Regulation of vascular endothelial barrier function by Epac, a cAMP activated exchange factor for Rap GTPase. Blood 2005; 105:1950-5.

 

11.   Vielhauer V, Stavrakis G, Mayadas TN. Renal Cell-Expressed TNF Receptor 2, not TNF Receptor 1 is Essential for the Development of Glomerulonephritis. J. Clin. Invest. 2005; 115:1199-1209.

 

12.  Hirahashi J*, Mekala D*, Van Ziffle J, Xiao L, Saffaripour S, Wagner DD, Shapiro SD, Lowell C, Mayadas TN. Mac-1 signaling via Src-family and Syk kinases results in elastase dependent thrombohemorrhagic vasculopathy. Immunity 2006; 25:271-83.

 

13.  Utomo A, Cullere X, Glogauer M, Swat W, Mayadas TN. Vav proteins in neutrophils are required for Fc?R mediated signaling to Rac GTPases and NADPH oxidase component p40phox. J. Immunol. 2006; 177:6388-97.

 

14.  Ghandour G, Cullere X, Alvarez A, Luscinskas FW, Mayadas TN. Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 but not VLA-4 integrin-mediated human T cell adhesion. Blood 2007; 110:3682-90.

 

15.  Sehrawat S, Cullere X, Patel S, Italiano J, Mayadas TN. Role of Epac1, an exchange factor for Rap GTPases, in endothelial microtubule dynamics and barrier function. Mol. Biol. Cell 2008; 19:1261-70.

 

16.  Tsuboi N, Asano K, Lauterbach M, Mayadas TN. Human neutrophil Fcγ receptors initiate and play specialized nonredundant roles in antibody-mediated inflammatory diseases. Immunity 2008; 28:833-46.

 

17.  Hirahashi J, Hishikawa K, Kaname S, Tsuboi N, Wang Y, Simon DI, Stavrakis G, Shimosawa T, Ling Xiao L, Nagahama Y, Suzuki K, Fujita T, Mayadas TN. Mac-1 (CD11b/CD18) is a critical molecular link between inflammation and thrombosis following glomerular injury. Circulation 2009; 120:1255-65.

 

18.  Sehrawat S, Ernandez T, Cullere X, Takahashi M, Ono Y, Komarova Y, Mayadas TN. AKAP9 regulation of microtubule dynamics promotes Epac1 induced endothelial barrier properties. Blood 2011; 117(2):708-18.

 

19.  Tsuboi N, Ernandez T, Li X, Nishi H, Cullere X, Mekala D, Hazen M, Köhl, J, Lee DM, Mayadas TN. Regulation of human neutrophil Fcγ receptor IIa by C5a receptor promotes inflammatory arthritis in mice. Arthritis and Rheumatism 2011; 63(2):467-78.

 

20.  Li X, Utomo A, Cullere X, Choi MM, Milner, Jr. DA, Venkatesh D, Yun S-H, Mayadas TN. 2011. The β-glucan receptor Dectin-1 activates the integrin Mac-1 in neutrophils via Vav protein signaling to promote Candida albicans clearance. Cell, Host & Microbe 2011; 10(6): 603-615

 

21.  Rosetti F, Tsuboi N, Chen K, Nishi H, Ernandez T, Sethi S, Croce K, Stavrakis G, Alcocer-Varela J, Gómez-Martin D, van Rooijen N, Kyttaris VC, Lichtman AH, Tsokos GC, Mayadas TN. 2012. Human lupus serum induces neutrophil-mediated organ damage in mice that is enabled by Mac-1 deficiency. J Immunol. 2012;189(7):3714-23.

 

22.  Chen K, Nishi H, Travers R, Tsuboi N, Martinod K, Wagner DD, Stan R, Croce K, Mayadas TN.  Endocytosis of soluble immune complexes leads to their clearance by FcγRIIIB but induces neutrophil extracellular traps via FcγRIIA in vivo. Blood; 2012; 120(22):4421-31. 

 

23.  Venkatesh V, Ernandez T, Rosetti F, Batal I, Cullere X, Zhang Y, García-Cardeña G, Stavrakis G, Horwitz B, Mayadas TN. TNFR2 induces IRF-1 dependent IFNβ autocrine signaling in endothelial cells to promote monocyte recruitment. Immunity 2013; 38(5):1025-37.

 

 

Selected Reviews and Chapters

1.     Mayadas TN, Tsokos G, Tsuboi N. Bench to Bedside Review Series: Mechanisms of immune complex mediated vascular injury. Circulation 2009;120:2012-24.

2.       Mayadas TN, Rosetti F, Ernandez T, Sethi S. Neutrophils: game changers in glomerulonephritis? Trends Mol Med 2010;16(8):368-78. PMCID: PMC2925238

3.     Ernandez T, Mayadas TN. 2010.  Chapter, Basis of Disease Pathogenesis: Humoral Pathogenesis. Fc Receptors and SLE. In: Systemic Lupus Erthematosus, 5th Edition. Ed: Robert G. Lahita. Elsevier, Inc.

4.     Lowell CA, Mayadas TN. Overview: Studying integrin in vivo. Methods Mol Biol. 2012; 757:369-97.

5.       Mayadas TN, Cullere X, Lowell CA. The multifaceted functions of neutrophils. Annual Review of Pathology: Mechanisms of Disease 2014; 9:181-218. 

6.       Al-Lamki RS, Mayadas TN. TNF Receptors: Signaling Pathways and Contribution to Renal Dysfunction. Kidney International 2014; in press.

 

 


Education:
U Rochester Med School, NY, 1990, PhD
PhD

Honors/Awards:
1996, Young Investigator Award for Excellence in Leukocyte Biology Research, Society of Leukocyte Biology
2001-2004 Established Investigator, American Heart Association
2009, 2013 Excellence in Tutoring Award, Harvard Medical School
2010, Stewart-Niewiarowski Award for Women in Vascular Biology
2012, Elsevier/Clinical Immunology Certificate of Excellence in Reviewing

Lab Members:
Xavier Cullere, PhD, Instructor

Hiroshi Nishi, MD, PhD, Research Fellow
Deepak Venkatesh, PhD, Research Fellow
Florencia Rosetti-Sciutto, MD, PhD, Research Fellow
Jan Herter, MD, Research Fellow
Ibrahim Batal, MD, Research Fellow
Kazuhiro Furuhashi, MD, PhD, Research Fellow
Paul Bennett, Technician
Gurpanna Saggu, PhD, Research Fellow