Cutting Edge: An Endogenous Pathway to Systemic Inflammatory Response Syndrome (SIRS)-Like Reactions through Toll-Like Receptor 4

Johnson, Geoffrey B.; Brunn, Gregory J.; Platt, Jeffrey L.

doi:10.4049/jimmunol.172.1.20

Cited by 222 publications

(187 citation statements)

References 41 publications

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“…Moreover, in vivo TLRs can also be stimulated by factors liberated after cell necrosis, which is a frequent event in high-grade gliomas. Additionally, TLR signaling can be desinhibited through degradation of the extracellular matrix (27). In glioma this may lead to a vicious cycle in which TLRs induce metalloproteinase activity that in turn facilitates further TLR signaling.…”

Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Simentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

342

328

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for highly malignant gliomas (World Health Organization grade III and IV) there is no successful treatment; patients have an average survival time of approximately 1 y after diagnosis. Glioma cells are highly invasive and infiltrate normal brain tissue, and as a result, surgical resection is always incomplete. Degradation of ECM by membrane-bound and secreted metalloproteases facilitates glioma invasion. In particular, the membrane-bound metalloproteases are pivotal for tumor invasion as they very efficiently digest extracellular matrix proteins and also activate secreted metalloproteases (1) like matrix metalloproteinase-2 (MMP-2, also known as gelatinase A), which is one of the major proteases involved in glioma invasion in mouse models (2) and probably also in humans (3). Hence, membrane-inserted metalloproteases like membrane type 1 matrix metalloproteinase (MT1-MMP) can enable gliomas to invade the brain parenchyma as single cells (4).Microglia are the intrinsic immune cells of the brain; they control the innate and the adaptive immune response in the CNS and are activated by inflammatory or other pathological stimuli (5). Activation of microglial toll-like receptors (TLRs) triggers the innate immune response and can initiate host-defense and tissue repair mechanisms, but also CNS inflammation, neurodegeneration, and trauma (5, 6). As microglial cells are attracted toward glioma in large numbers-glioma tissue consists of as much as 30% microglial cells-and because microglia density in gliomas positively correlates with malignancy, invasiveness, and grading of the tumors (7-9), we investigated if microglia may actively contribute to glioma expansion. Here, we show that soluble factors released from glioma stimulate microglial TLRs, resulting in microglial MT1-MMP expression via the TLR downstream signaling molecules MyD88 and p38 MAPK. In turn, MT1-MMP expression and activity in these immune cells promotes glioma cell invasion and tumor expansion. ResultsGlioma Associated Microglia Over-Express MT1-MMP. We analyzed the expression pattern of the matrix protease MT1-MMP in mouse and human gliomas and found the enzyme to be expressed predominantly in microglial cells closely associated with the tumors. Whereas tumor-free human brain samples showed virtually no MT1-MMP expression, we detected intense MT1-MMP labeling, especially in higher-grade gliomas. Importantly, in human samples, immunolabeling for the microglial marker Iba1 and for MT1-MMP largely overlapped [supporting information (SI) Fig. S1 A-D and Table S1]. Likewise, after injection of a human glioma cell line (U373 cells) into immunodeficient mice, we detected that microglia represent the predominant cell type contributing intratumoral MT1-MMP expression (see Fig. S1E).In our in vivo mouse model, the glioma cells were identified by stable expression of EGFP and microglial cells by immunolabeling for Iba1. In sections obtained from mice 2 weeks after intracerebral injection with isogenic glioma cells (GL261 cells), we found an increased density of mic...

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Section: Glioma Cells Induce Microglial Mt1-mmp Expression Via Tlr Simentioning

confidence: 99%

Gliomas induce and exploit microglial MT1-MMP expression for tumor expansion

Marković

Vinnakota

Chirasani

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

342

328

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“…8 Tumor tissue destruction mediated by gefitinib and other chemotherapeutic agents likely produces endogenous Toll-like receptor (TLR) ligands, including hyaluronan and heparan sulfate. 9, 10 We recently reported that gefitinib administration to mice along with the exogenous TLR ligand lipopolysaccharide (LPS) or various endogenous ligands induces interstitial lung disease. 11 Mice treated with gefitinib and LPS showed elevated expression of the transcription factor Fos-related antigen-1 (Fra-1, encoded by Fosl1) in lung tissues.…”

Section: Introductionmentioning

confidence: 99%

Gefitinib, but Not Erlotinib, is a Possible Inducer of Fra-1-mediated Interstitial Lung Disease

Takada

Matsuo

2012

Keio J. Med.

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Gefitinib is an anticancer drug developed to inhibit the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Two structurally-related EGFR tyrosine kinase inhibitors, gefitinib (Iressa) and erlotinib (Tarceva), are used as oral chemotherapy by patients with non-small-cell lung cancer. Immediately after introduction of gefitinib to clinical practice, interstitial lung disease was identified as a life-threatening adverse effect, although this condition can be well managed. It is still unclear whether gefitinib and other EGFR inhibitors induce similar adverse effects in lung. We previously established mouse models of interstitial lung disease in which gefitinib induces expression of Fosl1 (which encodes the AP-1 transcription factor Fra-1) in the presence of exogenous or endogenous Toll-like receptor ligands, leading to abnormal cytokine and chemokine expression. Here, we compared and monitored the effects of EGFR inhibitors gefitinib, erlotinib and AG1517 (PD153035) on the mRNA expression levels of Fosl1, Tnf and Ccl2. Unexpectedly, gefitinib, but not the other tyrosine kinase inhibitors, elicited the Fosl1 expression profile proposed to be predictive of interstitial lung disease, suggesting that gefitinib-induced interstitial lung disease is an off-target effect not elicited by erlotinib.

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“…This has already been tested in the case of immune stimulatory heparin sulphate (HS) fragments which are released from the ECM as a result of elastase activity (Brunn et al, 2005). Injection of elastase into the peritoneal cavity of mice caused the release of HS and induced sepsis, nearly as effectively as direct injection of HS or LPS (Johnson et al, 2004). Thus therapeutic measures aimed at…”

Section: Resultsmentioning

confidence: 99%