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The function of IL-17F in infection and inflammation

Zhou, Chunsheng (2021) The function of IL-17F in infection and inflammation. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The IL-17 family of cytokines is structurally distinct from other cytokine subclasses, and is composed of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25) and IL-17F. Among the IL-17 family, IL-17A and IL-17F share the most homology at the amino acid level. Both of these cytokines activate qualitatively similar downstream signals via binding with the IL-17RA:RC receptor complex but with different binding affinities. Consequently, similar disease susceptibility is observed in Il17a-/- and Il17f-/- mice in some animal models, for example autoimmune glomerulonephritis (AGN). However, IL-17A and IL-17F sometimes exhibit distinct biological activities in other settings, both infectious and autoimmune. This dichotomy is particularly illustrated in oropharyngeal candidiasis (OPC) and dextran sulfate sodium (DSS)-induced colitis. The mechanisms behind the surprisingly different in vivo functions of IL-17A and IL-17F remain largely underexplored. In order to further understand the function of IL-17F and potentially explore the mechanism by which IL-17A and IL-17F exhibit distinct roles in vivo, I took advantage of a naturally occurring human mutation that causes reduced binding affinity of IL-17F to the IL-17RA/RC receptor (IL-17F.S65L). In this dissertation, I describe the development of an IL-17F.S65L mouse strain (Il17fS65L/S65L), which I used to decipher the function of IL-17F in the settings of OPC, DSS colitis, and AGN. In Chapter 3, I show that Il17fS65L/S65L mice have increased susceptibility to OPC, which is similar to Il17a-/- but not Il17f-/- mice. In Chapter 4, I present data showing that Il17fS65L/S65L mice and Il17a-/- mice also have a similarly increased susceptibility to DSS colitis that contrasts with Il17f-/- mice. Surprisingly, however, the murine IL-17F.S65L mutation does not impact the development of AGN, despite the fact that Il17a-/- and Il17f-/- mice were both fully resistant to kidney damage in this disease model. For each model system, I present the outcomes and our current understanding of the underlying mechanisms. Overall, this dissertation research has helped to delineate the different in vivo activities of IL-17A and IL-17F and could potentially be beneficial for the development of IL-17F targeted therapy.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Zhou, Chunshengchz70@pitt.educhz700000-0002-9721-7948
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorGaffen, Sarah L.sarah.gaffen@pitt.edu0000-0001-8511-2041
Committee ChairKane, Lawrence P.lkane@pitt.edu0000-0001-5198-516X
Committee MemberBiswas, Partha
Committee MemberSt. Leger, Anthony J.Anthony.stleger@pitt.edu0000-0002-2547-200X
Committee MemberSfeir, Charles S.csfeir@pitt.edu0000-0003-3163-3292
Date: 1 June 2021
Date Type: Publication
Defense Date: 26 April 2021
Approval Date: 1 June 2021
Submission Date: 8 May 2021
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 141
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: IL-17F Colitis Oropharyngeal candidiasis
Date Deposited: 02 Jun 2021 02:38
Last Modified: 02 Jun 2021 02:38


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