EOSINOPHIL SECRETION · Secretion of inflammatory mediators from eosinophils and their tissue residing cell-free granules: mechanisms and implications in inflammation
FP7 — People (Marie Curie Actions)
- Duration
- 2015-01-01 → 2018-12-31
- EU contribution
- €100,000
- Participants
- 2
- Scheme
- MC-CIG
Lines connect the coordinator with its partners.
Results in brief
Secretion of inflammatory mediators from eosinophils and their tissue residing cell-free granules: mechanisms and implications in inflammation
Background: Asthma is one of the main allergic diseases affecting the global population, and presents with chronic mucosal inflammatory processes, mediated by white blood cells, such as mast cell and eosinophil. Mast cells release inflammatory mediators to orchestrate the immediate-early phase of the allergic response. Subsequent development of a late phase response is characterized by the recruitment and activation of several inflammatory cells, notably the eosinophils that respond to mast cell-released mediators and appear to play pivotal roles in the nature and extent of airway inflammatory responses. Apart from their renowned role in allergic reactions, mast cells and eosinophils are also involved in responses to host-defense against bacterial and parasitic infections, neoplastic diseases and fibrosis. Eosinophils and mast cells contain granules which are small particles packed with varied substances, ready for release outside the cells towards other cells or pathogens, such as viruses, bacteria and parasites. Although critical roles of these granule-driven proteins in host defense and in allergy pathology have been known for decades, the mechanisms that regulate their specific secretion are not well understood. In addition, this study also aims to reveal the inhibition machinery of eosinophils and mast cells, and the termination and resolution of the allergic inflammation to benefit asthma and allergic patients that suffer from over reactivity of these effector cells. Project objectives: A. Understanding the contribution of cytoskeletal machinery and cell adhesion molecules in eosinophil secretion. B. Understand the effect of inhibitory molecules, such as CD300a on eosinophils and mast cells-mediated allergy inflammation and resolution. These attributes will provide us excellent grounds to better understand the mechanisms by which eosinophils and mast cell contribute to allergy and asthma pathology and hopefully will help to design of new therapies targeting specifically the secretion from these effector cells. Main results achieved: A. Contribution of cytoskeletal machinery and cell adhesion molecules in eosinophil secretion. The study showed that the cytoskeletal machinery proteins, such as Rho and Rac are essential for eosinophil secretion. However, Rho-associated coiled-coil forming kinases (ROCKs), known downstream proteins of Rho A, serve as negative regulators of eosinophil secretion. In addition, we found that ROCKs regulate the surface expression of active cell adhesion molecule CD11b, which its activity is required for eosinophil secretion. These results were presented in several international scientific meetings and was recently published in Clin. Exp. Allergy. 2018 (Rho and Rac, but not ROCKs are required for secretion of human and mouse eosinophil-associated RNases. Shamri R, Young KM, Weller PF. Clin Exp Allergy. 2018 Oct 8, PMID: 30295352. B. Contribution of inhibitory molecules in allergic inflammation and resolution. The study showed that the expression of CD300a, an inhibitory receptor expressed on mast cells and eosinophils, is regulated during allergic inflammation and resolution. Using a mouse model of allergic inflammation, we found that in the absence of CD300a there is an enhancement of inflammation and a delayed resolution of allergic inflammation in mice. Moreover, CD300a regulates the expression of the resolution receptor, ALX/FPR2, that promotes inhibition of eosinophil and mast cell activity. These exciting results were recently published in J. Immunology. 2018 (Leukocyte CD300a Contribution to the resolution of Murine Allergic Inflammation Karra L, Singh Gangwar R, Shamri R, Puzzovio PG, Cohen-Mor S, Levy BD, Levi-Schaffer F. J Immunol. 2018, PMID: 30315138). Project potential impact and use: Current therapies for eosinophil- and mast cell-mediated pathologies, such as allergies and asthma, are based on non-specific blockers of the immune system, such as glucocorticoids or immunosuppressors and have significant adverse side effects. Newer potential therapies are currently concentrating on broadly blocking inflammation, eosinophil migration, eosinophil survival, rather than modulating eosinophil secretion. This study aims to reveal key players in inflammation and resolution of allergic inflammation and asthma to be considered as effective and specific targets for therapy purposes. Find more information about this project: https://medicine.ekmd.huji.ac.il/En/Publications/ResearchersPages/Pages/pages_francescal StudentsCV/revitalsha.aspx
Data: CORDIS, © European Union
Project objective
Eosinophils, both as end-stage effector cells and as Th2-immunomodulators, have the capacity to secrete varied inflammatory mediators, such as, cytokines and enzymes that are stored in their cytoplasmic secretory granules. Among them are the cationic proteins: major basic protein, eosinophil peroxidase, and the eosinophil RNases. In the last decade several studies, both in vitro and in vivo, have revealed a pivotal role for eosinophils and their granule content in immunomodulation, host defence and in pathology of eosinophil-associated diseases, such as allergy and asthma. Eosinophil secretion of granules content (e.g. degranulation) and the deposit of its cationic proteins are associated with a range of inflammatory disorders. Degranulation typically by means of piecemeal degranulation, is a controlled and selective process. In addition, at sites of inflammation, cytolysed eosinophils release cell-free granules, that reside in inflamed tissue.Recently, studies by me and my colleagues have revealed that beside secretion from intact cells, cell-free granules released from human and mouse eosinophils during lysis have the ability to secrete their content in response to cytokine stimulation in a cell free context. However, the mechanisms of these two methods of secretion and the key factors that participate in the degranulation process in intact eosinophils and especially in cell-free granules are poorly understood.The current proposal aims to explore the physiological functions of the newly discovered mode of secretion from eosinophil-derived cell free granules in allergic airway inflammation and the mechanisms by which integrins cooperate with elements of the cytoskeleton machinery in regulating chemokine-mediated degranulation in eosinophils. These studies will enhance our understanding of eosinophil degranulation, on the molecular and pathopysiological levels, and will provide potential targets for new directed therapies to treat eosinophil-associated diseases.
Original text from CORDIS.
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Data: CORDIS, © European Union