Neutrophils and Th17 cells in neuroinflammation

Date

2020

Authors

Wilson, Alicia

Journal Title

Journal ISSN

Volume Title

Publisher

Abstract

The IL-17 secreting CD4 T cell (Th17 cell) subset is an important active responder to extracellular pathogens in mucosal areas. While the absence of these Th17 cells leads to chronic mucocutaneous infections, the activity of Th17 cells has conversely been linked to the pathogenesis of many autoimmune diseases. These include rheumatoid arthritis and multiple sclerosis (MS). This thesis examines the role of Th17 cells in neuroinflammation, with a particular focus on how Th17 cells migrate and interact with other cells to promote inflammation. This was achieved using the experimental autoimmune encephalomyelitis (EAE) model, a commonly used rodent model of MS, in which both Th17 cells and neutrophils play pathogenic roles. Highlighting the importance of Th17 cells in the central nervous system (CNS) during neuroinflammation was the finding that despite increased circulating Th17 cells in the steady state, mice lacking expression of functional guanine exchange factor dedicator of cytokinesis 8 (DOCK8) were protected from development of EAE. This protection was achieved through a Th17 cell-specific neurotropic migration disadvantage, leaving Th17 cells unable to induce CNS disease. As a major function of Th17 cells is the recruitment of neutrophils, this complicated relationship was further explored. Activated neutrophils can extrude their DNA as highly cytotoxic neutrophil extracellular traps (NETs). If and how NETs impact Th17 cells, however, is unknown. Here it is shown that NETs, through their main protein component histones, are strong enhancers of Th17 cells through their induction of phosphorylation of signal transducer and activator of transcription 3 (STAT3) and upregulation of master Th17 cell transcription factor Retinoic-acid-receptor-related orphan nuclear receptor gamma (RORgt). This induction was reliant on Myeloid differentiation primary response 88 (MYD88) dependent toll-like receptor 2 (TLR2) signalling. Due to the correlation between the abundance of NETs and NET-related proteins with disease activity in MS, the possible role of NETs in EAE was explored. Increased levels of cell-free DNA and enhanced chemokine receptor 2 (CXCR2) expression were detected during EAE, indicating the presence of NETs in disease. While genetic knockouts of proteins involved in NET release did not impact EAE pathogenesis, inhibition of histones significantly reduced EAE severity. These data show, for the first time, a direct effect of NETs on Th17 cells and elucidate a novel pathway downstream of TLR2 leading specifically to Th17 cell induction. Further, these results suggest a beneficial effect of NET inhibition on EAE severity potentially through preventing NET induced exacerbation of encephalitogenic Th17 cells. This supports its further investigation as a novel treatment in MS.

Description

Keywords

Citation

Source

Type

Thesis (PhD)

Book Title

Entity type

Access Statement

License Rights

DOI

10.25911/5ea95835dedde

Restricted until