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  • Periodic Report Summary 1 - EOSINOPHIL SECRETION (Secretion of inflammatory mediators from eosinophils and their tissue residing cell-free granules: mechanisms and implications in inflammation)

Periodic Report Summary 1 - EOSINOPHIL SECRETION (Secretion of inflammatory mediators from eosinophils and their tissue residing cell-free granules: mechanisms and implications in inflammation)

Background:
Eosinophils are white blood cells, part of the immune system, known for their protective functions against parasites and their involvement in tissues damage in allergic diseases. Eosinophils 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. Many of eosinophil functions arise from the unique capacity of eosinophils, unlike other immune cells, to store hazard proteins, enzymes, cytokines, chemokines and growth factors in their intra-cellular granules, available for immediate release or degranulation. Having this preformed ammunition stored in granules allows eosinophils to contribute at the very beginning of the immune response, as well as at later time points during inflammation.
Release of eosinophil granule proteins has been demonstrated in diseased tissues, such as airways, heart, small intestine mucosa and skin from patients with acute and chronic eosinophilic disorders, such as, asthma, allergic rhinitis, hypereosinophilic syndromes, Churg-Strauss syndrome, atopic dermatitis, food sensitivity, eosinophilic gastroenteritis and eosinophilic esophagitis to name a few.

Mechanisms of granule protein secretion: The principal process of secretion from intracellular granules is by means of piecemeal degranulation (PMD), in which intact eosinophils can mobilize and selectively secrete their preformed granule proteins by transporting small packets within granule-derived secretory vesicles (smaller particles than granules to the cell surface. In addition to secretion by PMD, eosinophils have the capacity to release intact granules on cytolysis. Cytolysis is characterized by cell membrane rupture and liberation of intact membrane-bound granules. The presence of intact extra-cellular eosinophil granules in tissues and fluids has previously been documented in guinea pigs, mice, as well as human tissues in association with diverse disorders, including allergic asthma and rhinitis, dermatitis, helminth infections, eosinophilic esophagitis, and urticaria.
Interestingly, studies by me and colleagues indicated that these eosinophil-derived cell-free granules, from human and murine origin, express functional chemokine and cytokine receptors and secrete their content in response to physiological stimuli.

Although critical roles of these eosinophil-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.

Project objectives:
• Understanding the contribution of cell adhesion molecules as well as cell cytoskeletal machinery in eosinophil secretion/degranulation.
• Understand the implication of isolated granules in allergic inflammation.

These attributes will provide us excellent grounds to better understand the mechanisms by which eosinophils contribute to allergy and asthma pathology and hopefully will help to design of new therapies targeting specifically eosinophil secretion.




Project progression:
A combination of microscopically observations on cytoskeletal elements, such as actin, Rho and Rac, together with the use of cytoskeletal element inhibitors was applied in order to verify the role of each cytoskeletal element in eosinophil degranulation.

In addition, gene expression in eosinophils was carried out to reveal new players in eosinophil degranulation.


Main results achieved so far:
Rho and Rac, the small G-proteins that play key roles in the regulation of the rearrangements of the cell cytoskeleton required for cells division, survival, migration and adhesion. Our study aimed to understand the involvement of these cytoskeletal elements, such as Rho and Rac, in eosinophil secretion/degranulation.
Our study showed that Rho and Rac are essential for eosinophil secretion. Rho-associated coiled-coil forming kinases (ROCKs) are known downstream proteins, induced by Rho A, and are involved in cytoskeletal reorganization. It was previously shown by others that blocking of ROCKs attenuates eosinophil migration into lungs during airway inflammation. However, ROCKs role in granule content deposition (i.e. degranulation) from eosinophils was not addressed. Therefore, we examined the effect of the ROCK blocker, Y27632, on human and mouse eosinophil degranulation.

Our results show that effective concentrations of Y27632, did not reduce eosinophil degranulation, and even increased it in human and mouse eosinophils. In addition, Y27632 also increased spontaneous eosinophil degranulation (without stimulation). Moreover, degranulation enhancement by Y27632 was not due to an effect on actin dynamics. Rather, we found an increase in surface expression and active conformation of the cell adhesion molecule CD11b in human and mouse eosinophils. These results suggest that ROCKs are playing a negative regulatory role in degranulation of human and mouse eosinophils and that ROCK’s effect on degranulation is probably by increasing expression and activation state of adhesion molecule.


Project potential impact and use:

Current therapies for eosinophil-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 and/or survival, rather than modulating eosinophil secretion/degranulation.
We aim to reveal more cytoskeletal elements required specifically for eosinophil secretion/degranulation as targets for more specific and effective therapy of allergic diseases.


Find more information about this project : http://medicine.ekmd.huji.ac.il/En/Publications/ResearchersPages/Pages/revitalsha.aspx

Contact

Hani Ben Yehuda, (Head of EU desk)
Tel.: +97226586676
Fax: +972722447007
E-mail

Subjects

Life Sciences
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