Envisaging new targets for therapeutic intervention

The role of mast cells in controlling tissue homeostasis and pathogenesis

Professor Silvia Bulfone-Paus

Principal Investigator

Professor Silvia Bulfone-Paus

Tel: 0161 275 1591

Email: silvia.bulfone-paus@manchester.ac.uk

See: University profile | Lab members

Mast cell degranulation. An unstimulated mast cell (black arrow) and a degranulating mast cell (red arrow) can be seen in the endomysial connective tissue compartment surrounding the muscle fibres in a cryosection of mouse skeletal muscle. May-Grünwald Giemsa staining.

Mast cell degranulation. An unstimulated mast cell (black arrow) and a degranulating mast cell (red arrow) can be seen in the endomysial connective tissue compartment surrounding the muscle fibres in a cryosection of mouse skeletal muscle. May-Grünwald Giemsa staining.

Mast cells are powerful effector cells that play an important role in allergies, autoimmunity, inflammation and protective antibacterial and antiparasitic immune responses. Widely distributed throughout the body with a particular prevalence at sites in contact with the environment, such as skin, gut and airways, activated mast cells release a high number of preformed and newly synthesized mediators. These include cytokines, chemokines, histamine, serglycin proteoglycans and several mast cell specific proteases. This plethora of molecules enables mast cells to control both homeostasis in tissues as well as the initiation and maintenance of appropriate, selective, and effective immune responses.

Mast cell degranulation. Cultured peripheral blood derived human mast cells treated with IgE anti-IgE to induce degranulation. Immuno-staining for LAMP-2 (green fluorescence) shows degranulating/degranulated mast cells while immuno-staining for tryptase-β, a protease found inside mast cell granules, shows mast cell that have not yet degranulated (red fluorescence). Nuclei are stained with DAPI (blue fluorescence).

Mast cell degranulation. Cultured peripheral blood derived human mast cells treated with IgE anti-IgE to induce degranulation. Immuno-staining for LAMP-2 (green fluorescence) shows degranulating/degranulated mast cells while immuno-staining for tryptase-β, a protease found inside mast cell granules, shows mast cell that have not yet degranulated (red fluorescence). Nuclei are stained with DAPI (blue fluorescence).

Mast cells are critically involved in several skin disorders including both acute and chronic inflammatory processes. Our current research is therefore focused on understanding the mechanisms and requirements for selective secretion of mast cell mediators so as to control mast activation in pathological conditions. Our goals are 1) to investigate selected mechanisms and mediators which de-activate mast cell activation and degranulation; 2) to identify meanings and outcomes of mast cell interactions with other immune cells in disease; 3) to understand the functional significance of mast cell heterogeneity in tissue remodelling and disease chronicity. The characterization of mast cell-driven pathways in inflammation should enable to identify means of influencing acute and chronic inflammatory diseases.

Selected publications

Roldan NG, Orinska Z, Ewers H, Bulfone-Paus S. CD252 regulates mast cell-mediated, CD1d-restricted NKT-cell activation in mice. Eur J Immunol. 2015, doi: 10.1002/eji.201545879.

 

Bulfone-Paus S, Bahri, R. Mast cells as regulators of T cell responses. Front. Immun. Front. Immunol. 2015, 6:394. doi: 10.3389/fimmu.2015.00394.

 

Biethahn K, Orinska Z, Vigorito E., Goyeneche-Patino DA, Mirghomizadeh F, Föger N,

Bulfone-Paus S. miRNA-155 controls mast cell activation by regulating the PI3Kγ pathway and anaphylaxis in a mouse model. Allergy. 2014 69:752-62.

 

Sandig H, Jobbings CE, Roldan NG, Whittingham-Dowd JK, Orinska Z, Takeuchi O, Akira S, Bulfone-Paus S. IL-33 causes selective mast cell tolerance to bacterial cell wall products by inducing IRAK1 degradation. European Journal of Immunology. 2013, 43:979-88.

Föger N, Jenckel A, Orinska Z, Lee KH, Chan AC, Bulfone-Paus SDifferential regulation of mast cell degranulation versus cytokine secretion by the actin regulatory proteins Coronin1a and Coronin1b. The Journal of Experimental Medicine. 2011, 208:1777-87.

 

Orinska Z, Föger N, Huber M, Marschall J, Mirghomizadeh F, Du X, Scheller M, Rosenstiel P, Goldmann T, Bollinger A, Beutler BA, Bulfone-Paus SI787 provides signals for c-Kit receptor internalization and functionality that control mast cell survival and development. Blood. 2010, 116:2665-75.

 

Stelekati E, Bahri R, D’Orlando O, Orinska Z, Mittrücker HW, Langenhaun R, Glatzel M, Bollinger A, Paus R, Bulfone-Paus S. Mast cell-mediated antigen presentation regulates CD8+ T cell effector functions. Immunity. 2009, 3:665-76.

 

Orinska Z, Maurer M, Mirghomizadeh F, Bulanova E, Metz M, Nashkevich N, Schiemann F, Schulmistrat J, Budagian V, Giron-Michel J, Brandt E, Paus R, Bulfone-Paus SIL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities. Nature Medicine. 2007, 13:927-34.

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