Final Report Summary - EOSINOPHIL SECRETION (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
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