Regulation of the Inflammatory Response to Staphylococcus aureus-Induced Brain Abscess by Interleukin-10

Stenzel, Werner; Dahm, Julia; Sánchez‐Ruiz, Monica; Miletić, Hrvoje; Hermann, Manuel M.; Courts, Cornelius; Schwindt, Heinrich; Utermöhlen, Olaf; Schlüter, Dirk; Deckert, Martina

doi:10.1097/01.jnen.0000189836.48704.ca

Cited by 11 publications

(17 citation statements)

References 45 publications

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“…We show here that in TLR2 Ϫ/Ϫ mice, apoptosis of granulocytes was highly elevated, even after 3 weeks p.i., which reflects the high cellular turnover, a situation also characteristic for IL-10 Ϫ/Ϫ mice. 8 This is in line with observations of TLR2-mediated delay or inhibition of apoptosis in granulocytes. 60 -62 In contrast to our results obtained in TLR2 Ϫ/Ϫ mice, Kielian et al 28 have recently described lack of a significant impact for TLR2 on survival and bacterial load in a model of the early phase of S. aureus-induced murine brain abscess.…”

Section: Discussionsupporting

confidence: 78%

“…8 In the present study, TLR2 additionally regulated the production of proinflammatory mediators and chemokines during the course of disease. Thus, it is attractive to ascribe these chemokine-mediated effects to recruitment of granulocytes, macrophages, and T cells to the CNS, because leukocyte entry into the CNS was shown to be dependent on CCL2/CCR2 signaling.…”

Section: Discussionmentioning

confidence: 88%

“…Brain tissue was minced through a 70-m mesh sieve (BD Pharmingen), leukocytes were separated by Percoll gradient centrifugation (AmershamPharmacia, Freiburg, Germany), 34,35 and brain-derived leukocytes were subjected to double or triple immunofluorescence staining followed by flow cytometry as described previously. 8,9 Statistical Evaluation Student's t-test was performed to determine the significance of differences in the i.c. bacterial load, abscess size, the number of i.c.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…8 Briefly, the expression level of cytokines and chemokines and the endogenous control gene hypoxanthinguanine-phosphoribosyl-transferase (hprt) in the specimens was analyzed by real-time quantitative RT-PCR using the 5Ј-nuclease technology on an ABI PRISM 7300HT Sequence Detection System and the Mouse TaqMan pre-developed assay reagents (both from Applied Biosystems). The assay identification numbers are as follows: TNF, Mm00443258_m1; IFN-␥, Mm00801778_m1; IL-1␤, Mm00434228_m1; IL-6, Mm00446190_m1; IL-10, Mm00439616_m1; iNOS, Mm00440485_m1; CCL2, Mm00441242_m1; CCL3, Mm00441258_m1; CCL4, Mm00443111_m1; CCL5, Mm01302428_m1; CXCL5, Mm00436451_g1; and CXCL10, Mm00445235_m1 and for the internal control: hypoxanthine-guanine phosphoribosyl/transferase, Mm00446968_m1.…”

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

“…In addition to inflammatory leukocytes recruited to the CNS, brain resident cell populations, especially microglia and astrocytes, play central roles in the control of this infectious CNS disorder. 8,9,25 The precise involvement of different TLRs in brain abscess has not yet been defined in vivo. However, some recent data from in vitro research illustrate that TLR2 plays a pivotal role in recognition of peptidoglycan from S. aureus in microglial cells 26 and that TLR2 was required for a maximal cytokine response of primary astrocytes stimulated with peptidoglycan and S. aureus.…”

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confidence: 99%

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Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Stenzel

Soltek

Sánchez‐Ruiz

et al. 2008

The American Journal of Pathology

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Toll-like receptors (TLRs) play central roles in the innate reaction to bacterial products and transmit specific immune responses against these pathogens. TLRs are expressed on numerous cell types, including innate immune cells, and on astrocytes, neurons, and microglial cells of the central nervous system (CNS). Lipoproteins and lipopolysaccharides are specifically recognized by TLR2 and TLR4, respectively. We examined the in vivo role of TLR2 and TLR4 in Staphylococcus aureus-induced brain abscess. Phenotypically, 87% of TLR2 ؊/؊ mice and 43% of TLR4 ؊/؊ mice died whereas all wild-type (WT) mice recovered. Clearance of bacteria from the CNS was significantly delayed in TLR2 ؊/؊ mice compared with TLR4 ؊/؊ and WT animals. Recruitment of granulocytes and macrophages to the CNS, as well as microglial activation and expansion, was up-regulated in TLR2 ؊/؊ mice. Although inflammation persisted especially in the CNS of TLR2 ؊/؊ mice, but also of TLR4 ؊/؊ mice, WT mice terminated the infection more effectively. Collectively, these data show that the immune response to experimental S. aureus-induced brain abscess depends crucially on the recognition of S. aureus by TLR2 but that TLR4 is also required for an optimal intracerebral immune response in this disorder.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 88%

Section: Flow Cytometrymentioning

confidence: 99%

Section: Quantitative Real-time Pcrmentioning

confidence: 99%

mentioning

confidence: 99%

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Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Stenzel

Soltek

Sánchez‐Ruiz

et al. 2008

The American Journal of Pathology

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Regulation of the Inflammatory Response in Brain

Stenzel¹,

Alber²

2008

Handbook of Neurochemistry and Molecular Neurobiology

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Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice

et al. 2013

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Primary lymphoma of the central nervous system (CNS, PCNSL) is a specific diffuse large B cell lymphoma entity arising in and confined to the CNS. Despite extensive research since many decades, the pathogenetic mechanisms underlying the remarkable tropism of this peculiar malignant hematopoietic tumor remain still to be elucidated. In the present review, we summarize the present knowledge on the genotypic and phenotypic characteristics of the tumor cells of PCNSL, give an overview over deregulated molecular pathways in PCNSL and present recent progress in the field of preclinical modeling of PCNSL in mice. With regard to the phenotype, PCNSL cells resemble late germinal center exit IgM+IgD+ B cells with blocked terminal B cell differentiation. They show continued BCL6 activity in line with ongoing activity of the germinal center program. This together with the pathways deregulated by genetic alterations may foster B cell activation and brisk proliferation, which correlated with the simultaneous MYC and BCL2 overexpression characteristic for PCNSL. On the genetic level, PCNSL are characterized by ongoing aberrant somatic hypermutation that, besides the IG locus, targets the PAX5, TTF, MYC, and PIM1 genes. Moreover, PCNSL cells show impaired IG class switch due to sμ region deletions, and PRDM1 mutations. Several important pathways, i.e., the B cell receptor (BCR), the toll-like receptor, and the nuclear factor-κB pathway, are activated frequently due to genetic changes affecting genes like CD79B, SHIP, CBL, BLNK, CARD11, MALT1, BCL2, and MYD88. These changes likely foster tumor cell survival. Nevertheless, many of these features are also present in subsets of systemic DLBLC and might not be the only reasons for the peculiar tropism of PCNSL. Here, preclinical animal models that closely mimic the clinical course and neuropathology of human PCNSL may provide further insight and we discuss recent advances in this field. Such models enable us to understand the pathogenetic interaction between the malignant B cells, resident cell populations of the CNS, and the associated inflammatory infiltrate. Indeed, the immunophenotype of the CNS as well as tumor cell characteristics and intracerebral interactions may create a micromilieu particularly conducive to PCNSL that may foster aggressiveness of tumor cells and accelerate the fatal course of disease. Suitable animal models may also serve as a well-defined preclinical system and may provide a useful tool for developing new specific therapeutic strategies.

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Regulation of the Inflammatory Response to Staphylococcus aureus-Induced Brain Abscess by Interleukin-10

Cited by 11 publications

References 45 publications

Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Both TLR2 and TLR4 Are Required for the Effective Immune Response in Staphylococcus aureus-Induced Experimental Murine Brain Abscess

Regulation of the Inflammatory Response in Brain

Systems biology of primary CNS lymphoma: from genetic aberrations to modeling in mice

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