Translocator protein 18 kDa (TSPO): old dogma, new mice, new structure, and new questions for neuroprotection.

Abstract

The normal development and optimal functioning of the brain requires a vigilant immune surveillance system to detect and remove potential risk factors and prevent infection and tissue damage. Microglia are the resident immune cells and the frontline defenders responsible for the immune response of the brain. Resting microglia possess a ramified morphology with numerous thin processes that continuously sample the environment. In response to inflammatory signals, microglia become activated and transform their morphology into a thick, amoeboid-like shape. Activated microglia proliferate, migrate to sites of injury, and mediate a cascade of immune responses which protect tissues and maintain homeostasis. However, sustained activation of microglia in the diseased areas leads to over-production of toxic, pro-inflammatory cytokines, which aggravate neuronal damage. An interplay between environmental and genetic factors seems to be important for the interaction between neurons and microglia. The accumulation of neurotoxins affects microglia as well as neurons, and danger signals released from the degenerating neurons induce the microglia to enter a reactive state and overly recruited activated microglia exacerbatethe neurodegeneration process. Many familial neurodegenerative genes whose mutations cause neuronal toxicity also enhance pro-inflammatory responses in microglia. Therefore, hyper-activation of the immune cells in the nervous system, termed “neuroinflammation”, may not be the initiator of the neuropathologies, but rather may be considered as one of the major contributors to disease progression, intimately implicated in a variety of neuronal diseases. As such, the severity of neurodegeneration is often parallel to the level of neuroinflammation, and suppression of neuroinflammation yields neuroprotection in a broad spectrum of animal models of neurological disorders. These observations suggest that environment-gene interactions induce the vicious cycle of tissue damage through amplification of neuroinflammation. In addition to the characteristic and dynamic morphological changes, inflammatory activation of microglia induces a change in their gene expression profiles. Thus, immunological detection of marker proteins, such as IBA-1 or CD11b, has been commonly used to monitor microglia activation in the nervous system. However, the traditionally used immunohistochemical techniques have limitations and are not easily applicable to in vivo situations. Therefore, there is an imminent need for the development of biological markers and probes to monitor neuroinflammation in vivo. In this regard, high expression levels of translocator protein 18 kDa (TSPO) in the diseased state, which are especially predominant in activated microglia, have attracted increasing interest for its use as an imaging target for the visualization of injured brain areas and the monitoring of microglial activation.