Zhou, Chunsheng
(2021)
The function of IL-17F in infection and inflammation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
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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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| 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 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41049 |
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