Glioma‐associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline

Hu, Feng; Ku, Min-Chi; Marković, Darko; Dzaye, Omar; Lehnardt, Seija; Synowitz, Michael; Wolf, Susanne; Kettenmann, Helmut

doi:10.1002/ijc.28908

Cited by 102 publications

(89 citation statements)

References 41 publications

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“…Moreover, in a mouse model, the adjuvants MF-59 and CpG DNA (TLR9A) induce PTX-3 when injected into whole muscle in vivo , whereas Alum does not (29). The TLRAs MPLA and R848, as well as the TLRA-containing licensed vaccines we studied induced MMP-9, consistent with studies demonstrating TLR-mediated release of MMP-9 (64, 65). Interestingly, although Alum alone induced minimal MMP-9 release in whole blood (onefold), the Alum-adjuvanted HBV vaccine, comprised of Hepatitis B surface antigen as a viral like particle with Alum adjuvantation as well as yeast extract components that may trigger PRRs, induced a more robust response (two- to threefold).…”

Section: Discussionsupporting

confidence: 86%

Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures

Dowling

Ahmed

et al. 2016

Molecular & Cellular Proteomics

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Adjuvants boost vaccine responses, enhancing protective immunity against infections that are most common among the very young. Many adjuvants activate innate immunity, some via Toll-Like Receptors (TLRs), whose activities varies with age. Accordingly, characterization of age-specific adjuvant-induced immune responses may inform rational adjuvant design targeting vulnerable populations. In this study, we employed proteomics to characterize the adjuvant-induced changes of secretomes from human newborn and adult monocytes in response to Alum, the most commonly used adjuvant in licensed vaccines; Monophosphoryl Lipid A (MPLA), a TLR4-activating adjuvant component of a licensed Human Papilloma Virus vaccine; and R848 an imidazoquinoline TLR7/8 agonist that is a candidate adjuvant for early life vaccines. Monocytes were incubated in vitro for 24 h with vehicle, Alum, MPLA, or R848 and supernatants collected for proteomic analysis employing liquid chromatography-mass spectrometry (LC-MS) (data available via ProteomeXchange, ID PXD003534). 1894 non-redundant proteins were identified, of which ∼30 - 40% were common to all treatment conditions and ∼5% were treatment-specific. Adjuvant-stimulated secretome profiles, as identified by cluster analyses of over-represented proteins, varied with age and adjuvant type. Adjuvants, especially Alum, activated multiple innate immune pathways as assessed by functional enrichment analyses. Release of lactoferrin, pentraxin 3, and matrix metalloproteinase-9 was confirmed in newborn and adult whole blood and blood monocytes stimulated with adjuvants alone or adjuvanted licensed vaccines with distinct clinical reactogenicity profiles. MPLA-induced adult monocyte secretome profiles correlated in silico with transcriptome profiles induced in adults immunized with the MPLA-adjuvanted RTS,S malaria vaccine (Mosquirix™). Overall, adjuvants such as Alum, MPLA and R848 give rise to distinct and age-specific monocyte secretome profiles, paralleling responses to adjuvant-containing vaccines in vivo. Age-specific in vitro modeling coupled with proteomics may provide fresh insight into the ontogeny of adjuvant action thereby informing targeted adjuvanted vaccine development for distinct age groups.

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Section: Discussionsupporting

confidence: 86%

Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures

Dowling

Ahmed

et al. 2016

Molecular & Cellular Proteomics

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“…BMM from Ager −/− mice expressed lower levels of MMP9 and Cathepsin S when incubated with GL261 CM. These proteases are secreted by MG and MPs (26, 39, 40), are important in CNS tissue remodeling and have been shown to play a role in glioma angiogenesis and invasion (25, 41, 42). Interestingly, in GL261 gliomas, RAGE expression by both resident MG and infiltrating monocytes was important for angiogenesis in these tumors, suggesting that therapeutic strategies that only target infiltrating monocytes (and not MG) may not be adequate in preventing angiogenesis in these tumors.…”

Section: Discussionmentioning

confidence: 99%

RAGE Expression in Tumor-Associated Macrophages Promotes Angiogenesis in Glioma

et al. 2014

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Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anti-cancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in RAGE knockout (Ager−/−) mice. However, the improvement in survival in Ager−/− mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in non-invasive gliomas, where the expression of VEGF and pro-inflammatory cytokines were also lower in tumor-associated macrophages (TAM) in Ager−/− mice. Interestingly, reconstitution of Ager−/− TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis.

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“…The ability of glioma-produced versican to trigger increased TLR2 expression converts microglia into a pro-tumorigenic phenotype characterized by the upregulation of MT1-MMP and MMP9 expression. This feed-forward loop establishes an interdependent circuit of cellular interactions that increases glioma growth and invasion 81 .…”

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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Glioma‐associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline

Cited by 102 publications

References 41 publications

Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures

Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures

RAGE Expression in Tumor-Associated Macrophages Promotes Angiogenesis in Glioma

The role of microglia and macrophages in glioma maintenance and progression

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