Richard L. Stevens
Brigham and Women's Hospital
Smith Bldg., Rm. 616B
1 Jimmy Fund Way
Boston, MA 02115
My research program is focused on mast cells (MCs) which are tissue-residing immune cells that release a diverse array of biologically active molecules [including cytokines, chemokines, leukotrienes, prostaglandins, amines, proteases, and proteoglycans] when activated through their high-affinity IgE, low-affinity IgG, complement, and protease-activated receptors. Because MCs are present in sea squirts, these granulocytes evolved more than 500 million years ago before adaptive immunity. The fact that they have been conserved for so long documents their importance. In support of this conclusion, no human has been identified who lacks MCs, and studies carried out on MC-deficient mice revealed that these immune cells are essential for the efficient elimination of pathogens. For example, we showed that our transgenic mice that lack the MC-restricted granule protease mMCP-6 cannot combat K. pneumoniae infections of their peritoneal cavities (1), Pseudomonas aeruginosa infections of their skin, Trichinella spiralis infections of their muscles, and pneumovirus infections of their lungs relative to wild-type mice. mMCP-6 and its human ortholog hTryptase-beta also play important roles in prevent the internal accumulation of life-threatening fibrin/platelet clots (2). Despite their beneficial roles in coagulation and innate and acquired immunity, the presence of increased numbers of activated MCs in the skin of mastocytoma patients, in the bronchial airways of individuals with asthma and chronic allergies, in the skin of patients undergoing extensive fibrosis, in the intestines of helminth-infected individuals, in tumors of cancer patients, and in the joints of patients afflicted with rheumatoid arthritis suggest that these effector cells contribute substantially to the pathology that occurs in numerous clinical disorders. In this regard, we showed that exocytosed MC-restricted protease-heparin complexes play key roles in experimental arthritis, inflammatory bowel disease (3), and abdominal aortic aneurysms.
We demonstrated that mammalian MCs are a heterogeneous family of hematopoietic cells whose ultimate phenotype is dependent on the tissue microenvironment the mature cell eventually resides. In vitro and molecular biology approaches have been developed to identify the factors and receptors that regulate the differentiation and phenotypic properties of MCs. For example, we identified a novel cation-dependent, MC-restricted guanine exchange factor/phorbol ester receptor (designated as RasGRP4) that is important in arthritis and colitis (4). By varying the cytokines used to culture MCs (5), we have been able to induce bone marrow progenitor cells to differentiate and mature into populations of MCs that have varied phenotypes. We have identified a number of novel human and mouse MC-specific genes; we are now investigating why and how these genes and their transcripts are regulated as the MC's microenvironment is altered. Cis-acting elements and trans-acting DNA-binding proteins that regulate the transcription of these genes, and the RNA-binding proteins that regulate the stability of their transcripts are being identified. Transgenic mice have been created that differ substantially in the number of MCs that they have in their tissues. A transgenic/adoptive transfer approach also has been developed in order to address the role of varied MC-derived factors. Recombinant MC-derived proteases have been generated by my group in order to evaluate their physiologic function. Finally, what happens to T cells, epithelial cells, endothelial cells, neurons, fibroblasts, chondrocytes, and smooth muscle cells when they interact with MCs and their granule protease/proteoglycan complexes are being investigated.
1. Thakurdas SM, Melicoff E, Sansores-Garcia L, Moreira DC, Petrova Y, Stevens RL, Adachi R. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacteria infections. J Biol Chem. 2007;282:20809.
2. Prieto-García A, Zheng D, Adachi R, Xing W, Lane WS, Chung K, Anderson P, Hansbro PM, Castells M, Stevens RL. Mast cell restricted mouse and human tryptase•heparin complexes hinder thrombin-induced coagulation of plasma and the generation of fibrin by proteolytically destroying fibrinogen. J Biol Chem 2012;287:7834.
3. Hamilton MJ, Sinnamon MS, Lyng GD, Glickman JN, Wang X, Xing W, Krilis SA, Blumberg RS, Adachi R, Lee DM, Stevens RL. Essential role for mast cell tryptase in experimental colitis in mice. Proc Natl Acad Sci USA 2011;108:290.
4. Adachi R, Krilis SA, Nigrovic PA, Hamilton MJ, Chung K, Thakurdas SM, Boyce JA, Anderson P, Stevens RL. Ras guanine nucleotide releasing protein-4 (RasGRP4) involvement in experimental arthritis and colitis. J Biol Chem 2012, in press (see Journal website)
5. Kaieda S, Nigrovic PA, Seki K, Lee RT, Stevens RL, Lee DM. Synovial fibroblasts promote the expression and granule accumulation of tryptase via interleukin-33 and its receptor ST-2 (IL1RL1). J Biol Chem. 2010;285:21478.
Last Update: 1/6/2014