2007; Buchanan et al. 2010; Downes and Crack 2010; Lehnardt 2010). A main downstream event following pathogen recognition by microglia is the activation of NADPH-oxidase, which is a fundamental step for free radical release and other pro-inflammatory microglial actions (Block and Hong 2005; Qin et al. 2005; Cheret et al. 2008). This is a physiological and an appropriate response of microglia in order to eliminate pathogens and preserve tissue integrity. Nevertheless, recent studies suggest that in noninfectious diseases, such as stroke, SCI, and chronic neurodegenerative diseases,
microglia might mistake noninfectious disease-associated stimuli for the ones associated with infectious diseases, activating Inhibitors,research,lifescience,medical their killing mechanisms, which normally would be used to kill Inhibitors,research,lifescience,medical pathogens, but are unintentionally used to kill neurons (Block et al. 2007; Griffiths et al. 2007). It has been suggested that PRR activation underlies the mechanisms of cell demise in a number of noninfectious neural and nonneural diseases (Karin et al. 2006; Town et al. Inhibitors,research,lifescience,medical 2006; Griffiths et al. 2007; Lehnardt et al. 2007; Ziegler et al. 2007). For example, TLR-2 mediates CNS injury
in focal cerebral ischemia (Lehnardt et al. 2007) and activation of TLR-4 by a specific type of heat shock protein may be an endogenous molecular pathway common to many forms of neuronal injury (Lehnardt et al. 2008). TLR4 and CD14 are the primary LPS receptors in microglia (Lien et al. 2000) and in several experimental circumstances LPS induces microglia activation with neurotoxic consequences (Ling et al. 2006; Pei et al. 2007; Qin et al. 2007). Activation of other microglial PRRs is also involved in neurodegeneration (Cho et al. Inhibitors,research,lifescience,medical 2005; Block et al. 2007; Pei et al.
2007). These and other PH-797804 results suggest that noninfectious stimuli might bind microglial PRRs activating their killing mechanisms, which normally would be used to kill pathogens, but are unintentionally used to kill neurons in noninfectious CNS diseases (Block et al. 2007; Inhibitors,research,lifescience,medical Griffiths et al. 2007). From the experimental data described Calpain above, it is possible to infer that microglia are beneficial neuroimmune cells that might become detrimental in pathological conditions. It is likely that during neural disorders, a mosaic of detrimental and beneficial stimuli are released by altered neurons, glia, blood vessels, and other sources into the extracellular space, and microglial cells interpret them by using their surface receptors. We hypothesize that these harmful and beneficial stimuli are released into specific anatomical niches along damaged areas triggering both beneficial and deleterious actions of microglia. Depending on the CNS-affected area and disease’s etiology, both noxious and beneficial microglial phenotypes might coexist along the pathological environment.