Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

Disruption of Intestinal Th17 Signaling & the Microbiome Exacerbates Extra-Intestinal Pathologies

Castillo, Patricia Andrea (2019) Disruption of Intestinal Th17 Signaling & the Microbiome Exacerbates Extra-Intestinal Pathologies. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF (CastilloPAC_EtdPitt2019_v2.pdf)
Restricted to University of Pittsburgh users only until 13 September 2020.

Download (10MB) | Request a Copy

Abstract

IL-17 signaling to the intestinal epithelium is a critical regulator of the intestinal microbiome. There is a growing body of research linking alterations in both Th17 cells and the intestinal microbiome to extra-intestinal pathologies including hepatitis and neuroinflammation. For example, many patients with autoimmune, fulminant, and viral hepatitis exhibit increased systemic IL-17, and Il17ra-\- mice are protected in concanavalin A (Con A)-induced hepatitis, a murine model of immune-mediated hepatitis. In Multiple Sclerosis (MS), elevated IL-17 was found in CNS lesions, and disrupted Th17 differentiation in mice ameliorates disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. In addition, many patients with hepatitis and MS display an altered intestinal microbiome, and germ-free mice as well antibiotic-treated mice have decreased disease in Con A hepatitis and EAE. Despite these data, few studies have investigated how the relationship between enteric Th17 cells and the microbiome influences extra-intestinal pathologies.

Based on these reported links, we hypothesized that intestinal IL-17R signaling plays a critical role in mitigating hepatic and neuroinflammation. To test this, we generated intestinal epithelial specific IL-17RA knockout mice (Il17rafl/fl x villin cre+ mice). Because enteric Th17 signaling regulates the commensal microbiota, these mice exhibited an altered intestinal microbiome along with a subsequent expansion of intestinal Th17 cells. We then tested these mice in the Con A hepatitis model and EAE neuroinflammation model.

Our results showed that perturbation of intestinal IL-17RA signaling was sufficient to exacerbate both liver and neuroinflammation in a microbiome-dependent manner. Abrogation of intestinal IL-17RA disrupted the intestinal microbiota and promoted translocation of bacterial products to the liver. Together, this induced IL-18 production and subsequent lymphocyte activation and cell death to worsen hepatitis. In EAE, intestinal IL-17RA deficiency induced intestinal dysbiosis and increased intestinal Il17 and Csf2 and systemic responses in both cytokines. Preliminary data suggested a potential increase of inflammatory monocyte infiltration into the CNS, together exacerbating disease. These dissertation studies elucidate the differential role of enteric Th17 cells and the microbiome in extra-intestinal pathologies and more broadly in mucosal immunology. Moreover, it provides insight into novel therapeutic strategies that target the gut-liver and gut-brain axes.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Castillo, Patricia Andreapac85@pitt.edupac850000-0001-6290-4361
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorKolls, Jayjkolls1@tulane.edujkk23
Committee MemberHand, Timothytimothy.hand@chp.edu
Committee MemberBomberger, Jenniferjbomb@pitt.edu
Committee MemberMcGeachy, Mandymandymcgeachy@pitt.edu
Committee MemberRay, Anuradharaya@pitt.edu
Date: 13 September 2019
Date Type: Publication
Defense Date: 14 August 2019
Approval Date: 13 September 2019
Submission Date: 20 August 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 182
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: Th17 Microbiome Hepatitis Neuroinflammation
Date Deposited: 13 Sep 2019 15:12
Last Modified: 13 Sep 2019 15:12
URI: http://d-scholarship.pitt.edu/id/eprint/37394

Metrics

Monthly Views for the past 3 years

Plum Analytics


Actions (login required)

View Item View Item