Multiple Sclerosis (MS) is a debilitating autoimmune neurological disease. Th17 cells have emerged as key drivers of pathogenesis in chronic autoimmune disease and are increased in MS patients. Th17 cells are also critical for driving CNS inflammation in the murine model of MS, experimental autoimmune encephalomyelitis (EAE). Our previous work demonstrated that Th17 cells are dependent on signals from IL-23 for their proliferation and differentiation into effector cells capable of driving inflammation in EAE. Although Th17 cells are mostly considered as IL-17 producers, they have many additional functions and IL-17 is not always sufficient to drive disease. However, IL-23 is critical, and our goal is to understand the specific mechanisms by which IL-23 promotes Th17 functions in inflammatory disease. We have recently discovered a novel integrin that is expressed by effector Th17 cells in an IL-23-dependent manner, and required for EAE. Published reports describe increased expression of this integrin in a number of human inflammatory diseases, including MS. However, almost nothing is known about its functional importance in T cells, and in particular Th17 cells. Collectively, these data form the basis for our central hypothesis that this integrin is a key IL-23-driven molecule involved in determining the inflammatory activity of autoimmune Th17 cells. We now aim to interrogate the role of its expression in Th17-mediated inflammation, and thereby to validate this integrin as a novel Th17-directed therapeutic target.

Public Health Relevance

The inflammatory cytokine, IL-23, is critical for Th17 cell functions in autoimmune disease, but surprisingly little is known about the ways that it drives inflammation. We have identified a novel receptor that is expressed on Th17 cells in response to IL-23 in a model of multiple sclerosis. We now aim to investigate the regulation and functions of this molecule in promoting Th17 cell ability to cause disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI110822-04
Application #
9382848
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Esch, Thomas R
Project Start
2014-12-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
4
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Simpson-Abelson, Michelle R; Hernandez-Mir, Gerard; Childs, Erin E et al. (2017) CCAAT/Enhancer-binding protein ? promotes pathogenesis of EAE. Cytokine 92:24-32
Simon, Dennis W; McGeachy, Mandy J; Bay?r, Hülya et al. (2017) The far-reaching scope of neuroinflammation after traumatic brain injury. Nat Rev Neurol 13:171-191
Verma, Akash H; Richardson, Jonathan P; Zhou, Chunsheng et al. (2017) Oral epithelial cells orchestrate innate type 17 responses to Candida albicans through the virulence factor candidalysin. Sci Immunol 2:
Hernandez-Mir, Gerard; McGeachy, Mandy J (2017) CD73 is expressed by inflammatory Th17 cells in experimental autoimmune encephalomyelitis but does not limit differentiation or pathogenesis. PLoS One 12:e0173655
Du, Fang; Garg, Abhishek V; Kosar, Karis et al. (2016) Inflammatory Th17 Cells Express Integrin ?v?3 for Pathogenic Function. Cell Rep 16:1339-1351
Gaffen, Sarah L; McGeachy, Mandy J (2015) Integrating p38? MAPK immune signals in nonimmune cells. Sci Signal 8:fs5
Whibley, Natasha; Jaycox, Jillian R; Reid, Delyth et al. (2015) Delinking CARD9 and IL-17: CARD9 Protects against Candida tropicalis Infection through a TNF-?-Dependent, IL-17-Independent Mechanism. J Immunol 195:3781-92
Huppler, Anna R; Whibley, Natasha; Woolford, Carol A et al. (2015) A Candida albicans Strain Expressing Mammalian Interleukin-17A Results in Early Control of Fungal Growth during Disseminated Infection. Infect Immun 83:3684-92
Garg, Abhishek V; Amatya, Nilesh; Chen, Kong et al. (2015) MCPIP1 Endoribonuclease Activity Negatively Regulates Interleukin-17-Mediated Signaling and Inflammation. Immunity 43:475-87