Th17 and Cognitive Impairment: Possible Mechanisms of Action

Abstract

T helper 17 (Th17) cells represent a distinct population of immune cells, important in the defense of the organism against extracellular infectious agents. Because of their cytokine profile and ability to recruit other immune cell types, they are highly pro-inflammatory and are involved in the induction of several autoimmune disorders. Recent studies show that Th17 cells and their signature cytokine IL-17 have also a role in a wide variety of neurological diseases. This review article will briefly summarize the evidence linking Th17 cells to brain diseases associated with cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimer's disease (AD). We will also investigate the mechanisms by which these cells enter the brain and induce brain damage, including direct effects of IL-17 on brain cells and indirect effects mediated through disruption of the blood-brain barrier (BBB), neurovascular dysfunction and gut-brain axis. Finally, therapeutic prospects targeting Th17 cells and IL-17 will be discussed.

Keywords: IL-17 cytokine; Th17 cells; central nervous system; cognitive impairment; immune system; neuroinflammation.

Figure 1

Possible mechanisms of action of T helper 17 (Th17) and IL-17 in central nervous system (CNS). IL-17 is produced by Th17 and other cells, including natural killer cells, and γδ T cells. IL-17 receptor (IL-17R) is located on different cell types in the CNS. Circulating IL-17 provokes blood–brain barrier (BBB) disruption by altering TJ and cell-adhesion molecule expression on endothelial cells. The breakdown of BBB favors the entrance in the CNS of peripheral immune cells, including Th17 cells, neutrophils and other immune cells. Moreover, IL-17 allows cerebral endothelial cells to stop producing endothelial NO (eNOS), resulting in reduced cerebral blood flow (CBF) and endothelial dysfunction. In the CNS, IL-17 has direct effects on neurons and oligodendrocytes, inducing damage. Additionally, IL-17 signaling on microglia and astrocytes determines the expression of inflammatory cytokine, amplifies the production of reactive oxygen species (ROS) and promotes neutrophils chemotaxis and accumulation (see text).