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Receptor for advanced glycation endproducts mediates allergic airway inflammation via group 2 innate lymphoid cells

Oczypok, Elizabeth A (2015) Receptor for advanced glycation endproducts mediates allergic airway inflammation via group 2 innate lymphoid cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Half of all asthmatics suffer from allergic airway inflammation driven by type 2 immune responses in the lung, yet the molecular mechanisms that control early, initiating events in allergic asthma are poorly understood. Recently, scientists have discovered a new subset of innate cells that can trigger rapid type 2 allergic inflammation, even in the absence of an adaptive immune system. These cells, termed group 2 innate lymphoid cells (ILC2s), are activated by the epithelial alarmin, interleukin (IL)-33, and secrete copious amounts of the type 2 cytokines IL-5 and IL-13 to drive tissue eosinophilia, mucus hypersecretion, and airway hyperresponsiveness (AHR). It is unknown how these cells are recruited to the lung to promote allergic airway inflammation (AAI).
The receptor for advanced glycation endproducts (RAGE) is a proinflammatory receptor abundantly expressed in the lung. Previous studies have found that, in the absence of RAGE, IL-5 and IL-13 cytokine responses are impaired, and mouse lungs are completely protected from development of AAI and AHR. It was therefore hypothesized that RAGE was necessary for recruitment of type-2-cytokine-producing ILC2s to the lung during allergen challenge to initiate AAI.
The data presented here demonstrate that RAGE is, in fact, necessary for ILC2 accumulation in the lung after allergen challenge. Furthermore, this mechanism appears to be lung-specific and independent of RAGE expression on ILC2s themselves: tissues that do not normally express RAGE (i.e. gastrointestinal tract) mount normal ILC2-driven allergic responses even in RAGE KO mice. The ILC2-activating cytokine, IL-33, was also dependent on RAGE signaling, both upstream to trigger its release from epithelial cells and also downstream to mediate its inflammatory effects.
This is the first study examining a parenchymal factor in the recruitment of ILC2s to a specific organ. The exact mechanism by which this is occurring is still under investigation, but it may lead to the discovery of important new therapeutic targets early in the development of AAI.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Oczypok, Elizabeth Aeao14@pitt.eduEAO14
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairStolz, Donna Bdstolz@pitt.eduDSTOLZ
Thesis AdvisorOury, Tim Dtdoury@pitt.eduTDOURY
Committee MemberAlcorn, John F.jfa9@pitt.eduJFA9
Committee MemberRay, Anuradharaya@pitt.eduRAYA
Committee MemberShapiro, Steven Dshapiros@dom.pitt.eduSDS33
Date: 8 July 2015
Date Type: Publication
Defense Date: 25 June 2015
Approval Date: 8 July 2015
Submission Date: 7 July 2015
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 219
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: receptor for advanced glycation endproducts (RAGE); group 2 innate lymphoid cells (ILC2); IL-33; allergic airway inflammation (AAI); asthma
Date Deposited: 08 Jul 2015 15:27
Last Modified: 15 Nov 2016 14:29


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