CXCL16/CXCR6 Axis Drives Microglia/Macrophages Phenotype in Physiological Conditions and Plays a Crucial Role in Glioma

Abstract

Microglia are patrolling cells that sense changes in the brain microenvironment and respond acquiring distinct phenotypes that can be either beneficial or detrimental for brain homeostasis. Anti-inflammatory microglia release soluble factors that might promote brain repair; however, in glioma, anti-inflammatory microglia dampen immune response and promote a brain microenvironment that foster tumor growth and invasion. The chemokine CXCL16 is expressed in the brain, where it is neuroprotective against brain ischemia, and it has been found to be over-expressed in glioblastoma (GBM). Considering that CXCL16 specific receptor CXCR6 is diffusely expressed in the brain including in microglia cells, we wanted to investigate the role of CXCL16 in the modulation of microglia cell activity and phenotype, and in the progression of glioma. Here we report that CXCL16 drives microglia polarization toward an anti-inflammatory phenotype, also restraining microglia polarization toward an inflammatory phenotype upon LPS and IFNγ stimulation. In the context of glioma, we demonstrate that CXCL16 released by tumor cells is determinant in promoting glioma associated microglia/macrophages (GAMs) modulation toward an anti-inflammatory/pro-tumor phenotype, and that cxcr6ko mice, orthotopically implanted into the brain with GL261 glioma cells,survive longer compared to wild-type mice. We also describe that CXCL16/CXCR6 signaling acts directly on mouse glioma cells, as well as human primary GBM cells, promoting tumor cell growth, migration and invasion. All together these data suggest that CXCL16 signaling could represent a good target to modulate microglia phenotype in order to restrain inflammation or to limit glioma progression.

Meisoindigo Protects Against Focal Cerebral Ischemia-Reperfusion Injury by Inhibiting NLRP3 Inflammasome Activation and Regulating Microglia/Macrophage Polarization via TLR4/NF-κB Signaling Pathway

“…The inflammatory response that follows the initial ischemic insult is a key mechanism of secondary degeneration (Jin et al, 2010;Hamzei Taj et al, 2016). The critical roles of the NLRP3 inflammasome during stroke have been documented in many studies (Lepore et al, 2018; FIGURE 9 | Meisoindigo treatment suppresses the activation of the TLR-4/NF-κB/NLRP3 signaling pathway after stroke. (A) Representative western blot showing that Mei treatment reduces the expression and phosphorylation of TLR-4/NF-κB/NLRP3 signaling pathway-related proteins.…”

Zerumbone ameliorates behavioral impairments and neuropathology in transgenic APP/PS1 mice by suppressing MAPK signaling

“…Primary microglia were isolated from the cortex of newborn (postnatal day 0-2) C57BL/6 J mice by mild trypsinization as previously described [44]. Briefly, the cortex was chopped and digested into a single cell suspension which was incubated in DMEM/F-12 containing 10% FBS and 100 U/ml 1% penicillin/streptomycin.…”

Selective Upregulation of Transcripts for Six Molecules Related to T Cell Costimulation and Phagocyte Recruitment and Activation among 734 Immunity-Related Genes in the Brain during Perforin-Dependent, CD8+T Cell-Mediated Elimination of Toxoplasma gondii Cysts

“…The detection of increased levels of mRNA for the ligands for each of CXCR3 and CXCR6 suggests that both of these two chemokine receptors can function in the brains of the recipients of the immune T cells. Both CXCR3 and CXCR6 can be expressed on microglia and macrophages (16)(17)(18)(19). Since our recent studies demonstrated that both Iba1 ϩ microglia and Ly6C ϩ inflammatory macrophages accumulate to T. gondii cysts during CD8 ϩ cytotoxic T cell-mediated elimination of the cysts (13), it is possible that CXCR3 and CXCR6 mediate the accumulation of these phagocytes to the sites of anticyst immune responses once CD8 ϩ T cells initiate this process through their perforin-mediated activities.…”

“…ICOS is one of T cell costimulation molecules (14,15). CXCR3, CXCR6 (16)(17)(18)(19), and IL-18R1 are the molecules involved in recruitment and/or activation of microglia and macrophages (20,21). Therefore, the results of the present study suggest that ICOS plays an important role in activating CD8 ϩ cytotoxic T cells to initiate attacking T. gondii cyst-holding cells and that CXCR3, CXCR6, and IL-18R1 are involved in recruiting and activating the phagocytes corresponding to the T cellattacked cysts for eradicating bradyzoites located within the cysts for their elimination.…”