Abstract
The role of resident microglial cells in the pathogenesis and progression of glial tumors is still obscure mainly due to a lack of specific markers. Recently P2RY12, a P2 purinergic receptor, was introduced as a specific marker for microglial cells under normal and pathologic conditions. Here we analyzed the expression of P2RY12 in astrocytomas of various malignancy grades in relation to markers for M1 and M2 macrophage activation profiles by using two web-based glioma datasets and confocal immunohistochemistry to 28 astrocytoma samples grades II-IV. In the gliomas, P2RY12 immunoreactivity delineated CD68 negative cells with otherwise microglial features from CD68 positive tumor associated macrophages (TAMs). The presence of P2RY12 positive cells correlated positively with overall survival. P2RY12 mRNA levels and membrane-bound localization of P2RY12 were inversely correlated with increasing malignancy grade, and the expression site of P2RY12 shifted from cytoplasmic in low-grade gliomas, to nuclear in high-grade tumors. The cytoplasmic expression of P2RY12 was associated with the expression of M1 markers, characteristic of the pro-inflammatory macrophage response. In contrast, the nuclear localization of P2RY12 was predominant in the higher graded tumors and associated with the expression of the M2 marker CD163.We conclude that P2RY12 is a specific marker for resident microglia in glioma and its expression and localization correspond to tumor grade and predominant stage of M1/M2 immune response.
Highlights
Microglial cells are brain-specific tissue resident macrophages that are directly derived from yolk-sac erythromyeloid precursor cells (EMP) during embryonic development [19]
Reduction of membrane P2RY12 signal correlates with glioma grade The analysis of the public databases revealed that P2RY12 is mainly expressed in A II, while less in AA and GBM (Fig. 1a)
Double staining of P2RY12 with the pan- macrophage marker CD68 revealed a large population of CD68 negative, P2RY12 positive cells (CD68- P2RY12+) distinct from tumor associated macrophages (TAMs) (CD68+ P2RY12-) in all glioma samples (Fig. 1e)
Summary
Microglial cells are brain-specific tissue resident macrophages that are directly derived from yolk-sac erythromyeloid precursor cells (EMP) during embryonic development [19]. As major contributors to the immune status of the central nervous system (CNS) microglial cells scan the CNS for cellular debris by continuously protract and retract their cell processes [26]. Control (autopsy brains) 58 ± 13.3 2/2 tumor growth and prolonging patient survival [28, 39]. These cells are referred to as M1-like cells. TAMs that promote tumor progression are associated with an immunosuppressive response; contribute to tumor angiogenesis and proliferation, and are associated with poor clinical outcomes [10, 17, 33] and these cells are referred to as M2-like cells. TAMs are more similar to M2 than M1 macrophages [36]
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