Toll-like receptor (TLR) and inflammasome actions in the central nervous system

Abstract

During the past 10 years, much attention has been focused towards elucidating the impact of Toll-like receptors (TLRs) in central nervous system (CNS) innate immunity. TLR signaling triggers the transcriptional activation of pro-interleukin-1β (pro-IL-1β) and pro-IL-18 that are processed into their active forms by the inflammasome. Recent studies have demonstrated inflammasome involvement during CNS infection, autoimmune disease, and injury. This review will address inflammasome actions within the CNS and how cooperation between TLR and inflammasome signaling may influence disease outcome. In addition, the concept of alternative inflammasome functions independent of IL-1 and IL-18 processing are considered in the context of CNS disease.

Figure 1. Pathways involved in pro-IL-1β and pro-IL-18 expression

Induction of pro-IL-1β and pro-IL-18 occurs via TLR, NOD, or TNFR signaling in response to extracellular PAMPs, cytoplasmic PAMPs, or TNF-α, respectively.

Figure 2. Formation of NLRP3 or NLRP1 inflammasomes

Structurally, NLRs contain leucine rich repeats and a nucleotide binding domain (NBD). Only certain NLRs possess an N-terminal pyrin domain (i.e. NLRP3), whereas others do not (i.e. NLRP1). The N-terminal pyrin domain of NLRP3 interacts with the pyrin domain of ASC that serves to bridge the complex to pro-caspase-1. NLRP3 inflammasome oligomerization and subsequent caspase-1 activation is triggered by a diverse array of stimuli, including Aβ, ATP, ROS (reactive oxygen species), as well as various bacterial, fungal, and viral products.

Figure 3. TLR-inflammasome crosstalk

TLR and inflammasome action have been implicated in numerous infectious and neurodegenerative diseases, which are linked by the requirement for signal 1 (TLR) and signal 2 (inflammasome activation) to elicit IL-1β production. In turn, IL-1β can feed back to augment TLR-mediated effects.