Neural injury following stroke: are Toll-like receptors the link between the immune system and the CNS?

Abstract

The CNS can exhibit features of inflammation in response to injury, infection or disease, whereby resident cells generate inflammatory mediators, including cytokines, prostaglandins, free radicals and complement, chemokines and adhesion molecules that recruit immune cells, and activate glia and microglia. Cerebral ischaemia triggers acute inflammation, which exacerbates primary brain damage. The regulation of inflammation after stroke is multifaceted and comprises vascular effects, distinct cellular responses, apoptosis and chemotaxis. There are many cell types that are affected including neurons, astrocytes, microglia and endothelial cells, all responding to the resultant neuroinflammation in different ways. Over the past 20 years, researchers examining brain tissue at various time intervals after stroke observed the presence of inflammatory cells, neutrophils and monocytes at the site of injury, as well as the activation of endogenous glia and microglia. This review examines the involvement of these cells in the progression of neural injury and proposes that the Toll-like receptors (TLRs) are likely to be an integral component in the communication between the CNS and the periphery. This receptor system is the archetypal pathogen sensing receptor system and its presence and signalling in the brain following neural injury suggests a more diverse role. We propose that the TLR system presents excellent pharmacological targets for the design of a new generation of therapeutic agents to modulate the inflammation that accompanies neural injury.

Figure 1

A diagram of the Toll-like receptor (TLR) pathways, indicating MyD88-dependent signalling on the left, MyD88-independent signalling on the right and TLR 3 only signalling on the upper right.

Figure 2

A diagrammatic representation of the cell types involved in the inflammatory response to stroke. The left hand side of the image shows cells migrating to the CNS from the periphery, where the integrity of the blood–brain barrier (BBB) is disrupted. The centre of the image shows the response of the resident cells and the right hand panel shows infiltrating cells regardless of BBB integrity. Each of the numbers refers to Toll-like receptor (TLR) involvement and potential for pharmacological intervention. 1.Neutrophils aTLR 4 deficiency has been shown to be important in the recruitment of neutrophils expressing myeloperoxidase (MPO), following injury (Kilic et al., 2008). 2.Macrophages aTLR expression increases in inflammatory conditions associated with cerebral vasculature, such as aneurysm, and the receptors have a role in activating macrophages in response to TNF-α (Jayaraman et al., 2008). 3.T -cells aTLR activation of microglia leads to activation of Th 1 cells (Jack et al., 2005). bTreg release of anti-inflammatory IL-10 is MyD88 and TRIF dependent (Boonstra et al., 2006). cRelease of IL-10 from Tregs leads to a down-regulation of MyD88 (Dagvadorj et al., 2008). dTLR 8 modulated the Treg response to injury (Peng et al., 2005). eTh1 cell induction is dependent on MyD88 pathways, while Th2 cells are activated via MyD88 independent pathways (Lin et al., 2004). 4.Astrocytes aTLR activation on astrocytes can lead to expression of MMP-9 and contribute to BBB breakdown (Hsieh et al., 2010). 5.Neurons aTLR 2 and 4 mediate neuronal death during stroke (Ziegler et al., 2007). 6.Glia aTLR 2 is expressed on microglia following ischemia and mice lacking TLR 2 suffer a smaller infarct (Lehnardt et al., 2007). bTLR 3 on glia releases neuroprotective mediators following inflammation (Bsibsi et al., 2006). 7.Myeloid dendritic cells aMyeloid related proteins 8 and 14 are thought to act as TLR ligands and increase recruitment of infiltrating myeloid cells (Ziegler et al., 2007). bIn response to inflammation TLR pathways mediate maturation (Ueda et al., 2005) of myeloid cells. 8.Endothelium aTLR 4 expression on the endothelium increases following sub-arachnoid haemorrhage (Zhou et al., 2007). bTLR ligands in the circulation lead to altered function of the BBB (Singh and Jiang, 2004). cTLR 4 on non-haematopoietic cells is important for controlling the CNS inflammatory response to peripheral stimuli (Chakravarty and Herkenham, 2005).