Brigham and Women's Hospital
New Research Building, Room 752o
77 Avenue Louis Pasteur
Boston, MA 02115
Lab Members: 8 Postdoctoral fellows, 1 Graduate Student
My laboratory is broadly interested in delineating mechanisms of inflammation in response to tissue injury. A primary objective is to understand neutrophil-dependent recruitment and activation in the context of IgG-mediated autoimmune diseases. In this regard, we study how neutrophil opsonic receptors, FcγRs (binds complexed IgG) and Mac-1 (CD11b/CD18, binds complement C3) regulate neutrophil recruitment and activation in response to immune complex deposition. We also focus on identifying the intracellular signals relayed by these receptors to trigger specific effector functions. In addition, related to our interest in vascular inflammation, my lab focuses on delineating the contribution of the two endothelial TNF receptors, TNFR1 and TNFR2, in immune-mediated glomerular inflammation, and elucidating molecular pathways that link cAMP to enhanced resistance of the endothelium to macromolecules.
My lab exploits genetically engineered mouse models, molecular and biochemical approaches in primary cultured cells, in vivo models of inflammation relevant to human disease and real-time imaging of neutrophil-vessel wall interactions for our studies. My research groups has i) Defined a novel function for Mac-1 in triggering neutrophil apoptosis following complement mediated phagocytosis, which has implications for the resolution of inflammation; ii) Identified a role for Mac-1 in linking inflammation and thrombosis in vivo; iii) Expressed human neutrophil FcγRs, FcγRIIA and the GPI-linked FcγRIIIB selectively on neutrophils of mice lacking their endogenous murine FcγRs, to understand the function of these uniquely human FcγRs in vivo. Studies in these humanized mouse models suggest a paradigm in IgG mediated diseases wherein neutrophils are recruited and promote tissue injury through their own FcγRs. We also demonstrated that FcγRIIA and FcγRIIIB play specialized context-dependent roles in neutrophil recruitment in vivo. These humanized mouse models continue to reveal distinct functions for each of these FcγRs that may provide an explanation for why human neutrophils constitutively express two activating FcγRs; iii) Delineated the contribution of FcγRs and Mac-1, and their signaling transduction pathways, in neutrophil cytotoxicity in vivo at steps downstream of neutrophil recruitment. Therapeutic targeting of these steps would represent an attractive strategy for combating immune mediated injury; iv) Identified differential roles for the two TNF receptors (TNFR1 and TNFR2) in the pathogenesis of chronic antibody-induced glomerulonephritis. These are active areas of investigation in the laboratory.
In the area of endothelial permeability we aim to elucidate how this process is regulated by cAMP, which was throught to control cellular processes principally through Protein kinase A (PKA). Relatively recently, cAMP was shown to activate Epac1, a cAMP responsive guanine exchange factor for Rap GTPases. Our work demonstrated that Epac1 activation markedly enhanced endothelial barrier function and counteracted agonist-induced hyperpermeability by modulating the actin and microtubule cytoskeleton. Our current focus is to assess the importance of compartmentalization of cAMP signaling in the regulation of Epac1 mediated barrier enhancement.
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.
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.
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.
Utomo A, Cullere X, Glogauer M, Swat W, Mayadas TN. Vav proteins in neutrophils are required for FcγR mediated signaling to Rac GTPases and NADPH oxidase component p40phox. J. Immunol. 2006; 177:6388-97.
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.
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.
Last Update: 2/19/2014