Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion

Vinnakota, Katyayni; Hu, Feng; Ku, Min-Chi; Georgieva, Petya B.; Szulzewsky, Frank; Pohlmann, Andreas; Waiczies, Sonia; Waiczies, Helmar; Niendorf, Thoralf; Lehnardt, Seija; Hanisch, Uwe‐Karsten; Synowitz, Michael; Marković, Darko; Wolf, Susanne; Glaß, Rainer; Kettenmann, Helmut

doi:10.1093/neuonc/not115

Cited by 122 publications

(152 citation statements)

References 51 publications

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“…Microglia were labelled using goat-anti-Iba1 antibody (1:400, Abcam) followed by the secondary antibody anti-goat Cy5 (1:250 Jackson Laboratories) described elsewhere (Vinnakota et al, 2013). For Iba1 reactivity measures (mean fluorescence intensity per area) DAPI was used as reference.…”

Section: Microglia Fluorescence Intensitymentioning

confidence: 99%

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Mattei

Djodari-Irani

Hadar³

et al. 2014

Brain, Behavior, and Immunity

166

130

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Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia.We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1β and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1β production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.3

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Section: Microglia Fluorescence Intensitymentioning

confidence: 99%

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Mattei

Djodari-Irani

Hadar³

et al. 2014

Brain, Behavior, and Immunity

166

130

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“…GL261 glioma cells were implanted into the cortex/striatum region of 8 to 10-week-old mice [26]. As control, a stab wound lesion was induced in the contralateral cortex by inserting a syringe without injecting tumor cells.…”

Section: Methodsmentioning

confidence: 99%

“…Glioma-associated macrophages/monocytes (GAMPs) also invade into glioma from the blood system. GAMs and GAMPs have been shown to promote glioma growth and invasion and thus are tumor-supportive cells [5, 15, 26]. Glioma-derived factors reprogram microglial cells into a tumor-supporting, immuno-suppressed phenotype, that participates in remodeling of the extracellular matrix to promote infiltrative growth of glioma [7].…”

Section: Introductionmentioning

confidence: 99%

Glioma-associated microglia and macrophages/monocytes display distinct electrophysiological properties and do not communicate via gap junctions

Richter

Wendt

Georgieva

et al. 2014

Neuroscience Letters

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Both brain-resident microglia and peripheral macrophages/monocytes infiltrate into glioma and promote glioma growth. In the present study we analyzed coupling and membrane currents in glioma-associated microglia and macrophages/monocytes and compared this to control and stab wound-associated microglia. Using the Cx3cr1GFP/wt Ccr2RFP/wt knock-in mouse line, we distinguished membrane currents of glioma-associated microglia and macrophages/monocytes in acute brain slices prepared 14-16 days after inoculation of GL261 glioma cells. The current profile of microglia showed inward rectifying currents reminiscent of an intermediate activation state when compared to other disease models or cell culture. Macrophages/monocytes showed a higher specific outward conductance and a significantly lower capacitance indicative of a smaller membrane area than microglia. As controls, we also recorded currents from control microglia and stab wound-associated microglia. Since there are reports of microglial coupling in vitro, we injected biocytin into these cells and analyzed for cell coupling after fixing the slices and processed for biocytin labeling with Cy3- conjugated-Streptavidin. Neither control microglia nor glioma-associated microglia and macrophages/monocytes nor stab wound-associated microglia showed any sign of coupling. Moreover, performing qRT-PCR revealed that no connexin43 was detectable on isolated and sorted glioma-associated microglia and macrophages/monocytes, indicating that these cells are not part of a coupled network.

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“…TLR2 forms heterodimers with TLR1 and TLR6, which is important for modulating MT1-MMP expression; deletion of both TLR1 and TLR6 results in reduced MT1-MMP expression. In addition, treatment with TLR2-neutralizing antibodies reduces glioma-induced microglial MT1-MMP expression and attenuates glioma growth 79 .…”

Section: Tams and High-grade (Malignant) Gliomamentioning

confidence: 99%

The role of microglia and macrophages in glioma maintenance and progression

2015

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There is a growing recognition that gliomas are complex tumors composed of neoplastic and non-neoplastic cells, which each individually contribute to cancer formation, progression and response to treatment. The majority of the non-neoplastic cells are tumor-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, that create a supportive stroma for neoplastic cell expansion and invasion. TAMs are recruited to the glioma environment, have immune functions, and can release a wide array of growth factors and cytokines in response to those factors produced by cancer cells. In this manner, TAMs facilitate tumor proliferation, survival and migration. Through such iterative interactions, a unique tumor ecosystem is established, which offers new opportunities for therapeutic targeting.

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Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion

Abstract: Our results thus show that activation of TLR2 along with TLRs 1 and/or 6 converts microglia into a glioma supportive phenotype.

Cited by 122 publications

References 51 publications

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Minocycline rescues decrease in neurogenesis, increase in microglia cytokines and deficits in sensorimotor gating in an animal model of schizophrenia

Glioma-associated microglia and macrophages/monocytes display distinct electrophysiological properties and do not communicate via gap junctions

The role of microglia and macrophages in glioma maintenance and progression

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