Toll-like receptor 2 mediates CNS injury in focal cerebral ischemia

Abstract

Toll-like receptors (TLR) recognize molecular structures associated with pathogens as well as host-derived components and initiate an inflammatory innate immune response. Microglia represent the resident immune host defense and are the major inflammatory cell type in the central nervous system (CNS). We show here that TLR2-deficient mice develop a decreased CNS injury compared to wild type mice in a model of focal cerebral ischemia. TLR2 mRNA is up-regulated in wild type mice during cerebral ischemia. In ischemic brains, TLR2 protein is expressed in lesion-associated microglia. Absence of TLR2 does not affect the recruitment of granulocytes to the infarct region. We conclude that TLR2 in microglia propagates stroke-induced CNS injury.

Introduction

Injury in the central nervous system (CNS) is associated with inflammation that is essential for clearing of non-viable cells and restoring normal function. However, it has become evident that inflammation in the CNS also contributes to neuronal injury and exacerbates tissue injury (Lucas et al., 2006).

The innate immune system is the first line of defense against invading microorganisms and is based on a range of receptors, including Toll-like receptors (TLR), which recognize molecular structures associated with pathogens. Activation of TLRs leads to the induction of an inflammatory innate immune response and the priming of antigen-specific adaptive immunity. Thirteen TLR orthologues, of which ten are expressed in humans, and their corresponding ligands, including bacterial and viral constituents, have been identified (Akira et al., 2006). TLR2 recognizes cell wall components derived from Gram-positive bacteria. However, while the original homologue Toll serves an innate immune function in the adult Drosophila fly, its critical patterning function during embryogenesis requires an endogenously produced ligand (Stein et al., 1991). Accordingly, several endogenous activators of mammalian TLRs, including heat shock proteins and extracellular matrix components, have been identified (Beg, 2002).

Stroke is one of the leading causes of death and disability today. A common form of stroke is cerebral ischemia, in which reduction of blood flow causes injury to the brain. Microglia, the resident innate immune cells of the CNS, are the first inflammatory cells that respond to cerebral ischemia. Activated microglia transform into an ameboid shape and secrete proinflammatory molecules. Since some of these are neurotoxic, it has been suggested that activated microglia may contribute to acute brain injuries such as cerebral ischemia (Dirnagl et al., 1999). However, the molecular mechanisms that underlie microglial activation in this context are unknown. Recently, we have shown that TLR2 expressed in microglia is critical for neuronal injury in the context of CNS inflammation (Lehnardt et al., 2006).

In the present study, we investigated whether acute CNS injury caused by focal cerebral ischemia differed in mice that lack a functional TLR2 signaling pathway compared to wild type mice. Our data suggest a critical role for TLR2 in stroke.