The Role of Dual-Specific CysLT1/P2Y Receptor of Brain Mast Cells in Multiple Sclerosis

Joshua A. Boyce

Brigham and Women's Hospital

Funded in December, 2001: $300000 for 7 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

ABSTRACT

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The Role of Dual-Specific CysLT1/P2Y Receptor of Brain Mast Cells in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic, progressive, debilitating disease with a variable prognosis and high rates of morbidity and mortality. The goal of this proposal is to understand the role of the CysLT1 receptor and its proinflammatory and neurogenic ligands (cysteinyl leukotrienes [cys-LTs] and uridine diphosphate [UDP], respectively) in regulating the effector function of brain mast cells (MCs) in experimental allergic encephalomyelitis (EAE), a mouse model of MS.

Cys-LTs are major mediators of microvascular leakage. MCs are one of the few immune cell types found in the brain and central nervous system under normal circumstances, and are found in the plaque lesions of patients with MS. A key role for MCs in the severity and progression of MS is suggested by the EAE model. We recently demonstrated that human umbilical cord blood-derived MCs express the CysLT1 receptor. Unexpectedly, the CysLT1 receptor binds and is activated not only by cys-LTs, but also by UDP, which is among the ligands potentially involved in triggering neurogenic inflammation. Moreover, preliminary data indicate that stimulation of human MCs with either cys-LTs or with UDP promotes their release of several proinflammatory cytokines and chemokines, including tumor necrosis factor (TNF)-α, and macrophage inflammatory protein (MIP)-1β.

These findings suggest that stimulation of MCs in the brain in vivo by the CysLT1 receptor ligands could promote lymphocyte recruitment, inflammation, and tissue destruction. We have confirmed that mouse MCs, like their human counterparts, express the CysLT1 receptor, and have developed mice with targeted disruptions of the CysLT1 receptor, and of leukotriene C4 synthase (LTC4S), the terminal enzyme required for the biosynthesis of cys-LTs. We will use these mice to study the effects of the respective gene disruptions on the onset, progression, and severity of EAE. We anticipate that these studies will yield valuable information concerning the role of MCs, the potential mechanisms that control their activation and effector behavior, the specific potential roles of cys-LTs, nucleotides, and their receptors in these processes, and the potential for targeted therapeutic interventions.

SELECTED PUBLICATIONS

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Jiang Y., Kanaoka Y., Feng C.L., Nocka K., Rao S., and Boyce J.A.  Cutting edge: Interleukin 4-dependent mast cell proliferation requires autocrine/intracrine cysteinyl leukotriene-induced signaling.  J Immunol. 2006 Sep 1;177(5):2755-9.

Feng C.L., Beller E.M., Bagga S., and Boyce J.A.  Human mast cells express multiple EP receptors for prostaglandin E2 that differentially modulate activation. Blood. 2006 Apr 15;107(8):3243-50.

Lin D.A. and Boyce J.A.  IL-4 regulates MEK expression required for lysophosphatidic acid-mediated chemokine generation by human mast cells.  J Immunol. 2005 Oct 15;175(8):5430-8.

Feng C., Mery A.G., Beller E.M., Favot C., and Boyce J.A.  Adenine nucleotides inhibit cytokine generation by human mast cells through a Gs-coupled receptor.  J Immunol. 2004 Dec 15;173(12):7539-47.

Bagga S., Price K.S., Lin D., Friend D.S., Austen K.F., and Boyce J.A.  Lysophosphatidic acid accelerates the development of human mast cells. Blood. 2004 Dec 15;104(13):4080-7.

Lora J.M., Al-Garawi A., Pickard M.D., Price K.S., Bagga S., Sicoli J., Hodge M.R., Gutiérrez-Ramos J.C., Briskin M.J., and Boyce J.A. FcεRI-dependent gene expression in human mast cells is differentially controlled by T helper type 2 cytokines.  J Allergy Clin Immunol. 2003 Dec;112(6):1119-26

Mellor E.A., Frank N., Soler D., Hodge M.R., Lora J.M., Austen K.F., and Boyce J.A.   Expression of the type 2 receptor for cysteinyl leukotrienes (CysLT2R) by human mast cells: Functional distinction from CysLT1R.  Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11589-93.

Mellor E.A., Austen K.F., and Boyce J.A.  Cysteinyl leukotrienes and uridine diphosphate induce cytokine generation by human mast cells through an interleukin 4-regulated pathway that is inhibited by leukotriene receptor antagonists. J Exp Med. 2002 Mar 4;195(5):583-92.