Microglia and brain macrophages: An update.

Current immunohistochemical techniques have made the identification of microglia possible in routinely processed tissue sections from human brains. Previous studies have indicated that almost no neurological diseases exist without microglial activation. Activated microglia often secrete inflammatory cytokines in various diseases, including Alzheimer's disease, but microglial activation is not always associated with inflammation. The equation microglial activation means "neuroinflammation" is absurd and misleading. Neuropathologists are in the best position to provide clarity to end the existing confusion. The functions of microglia in the non-diseased brain probably include a role in synaptic maintenance, but defects in the expression of specific molecules on microglia can also cause leukoencephalopathy, such as Nasu-Hakola disease (NHD) and hereditary leukoencephalopathy with spheroids (HDLS). "Microgliopathies" is a new term used to designate conditions where microglial dysfunction is primary and at the center of the disease process. The molecules responsible are DAP12 or TREM2 in NHD and CSF1R in HDLS, respectively, but further studies are needed to clarify how exactly these microglial molecules influence the pathogenesis of axonal and myelin loss. Diffusely infiltrating glial tumors showing microglial differentiation (true microglioma) are exceedingly rare but recent evidence suggests that they indeed exist, although their molecular genetic characterization is still lacking. Participation of the expert neuropathology community will be required to identify additional cases and provide the latter. A large number of tumor-associated macrophages (TAMs), which are partly derived from microglia, have been observed in glioblastomas. In TAMs, the expression of M2-like molecules is higher than that of M1-like molecules, but the number and differentiation state of TAMs vary in the intratumoral area and with the type of macrophage markers used. In future studies, we should focus on the morphological and molecular alterations of the microglia that are specific to the disease where they are observed.