Unknown,Transcriptomics,Genomics,Proteomics

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Regulation of tumor associated macrophages by cooperative inflammatory signaling

ABSTRACT: Tumor associated macrophages show signs of both, classical pro-inflammatory as well as alternative macrophage activation. The aim of this study was to compare TAMs across tumor types, to characterize their phenotype in detail and to identify the signaling nodules involved regulating classical and alternative activation traits. To identify gene expression profiles and pathways differentially activated in tumor-associated macrophages (TAMs) we isolated TAMs from in vivo animal models of EG7 thymoma (n=3), glioma (n=3) and neuroblastoma (n=3) by tumor digestion and subsequent enrichment of CD11b+ cells using Miltenyi magnetic beads. Thymomas grown in WT or Myd88-/- mice (n=5 per group) were used to identify TLR/IL1R dependent signaling in TAMs. RNA extracted from CD11b+ TAMs was analyzed using the Affymetrx HT_MG-430_PM arrays. For in-depth analysis of the role of inflammatory signaling by TNFR1 (Tnfrsf1a) and/or Myd88, EG7 TAM populations A (CD11b+, Ly6G-, Ly6C+, MHCII-) and C (CD11b+, Ly6C-, MHCII+) were isolated by flow cytometric sorting from WT, TNFR1-/-, Myd88flox/flox; Tie2-Cre and TNFR-/-; Myd88flox/flox; Tie2-cre mice and extracted RNA was analyzed by microarray using the Mouse Gene 2.0 GeneChip arrays (n=2 per genotype and population).

ORGANISM(S): Mus musculus

SUBMITTER: Geoffrey Neale

PROVIDER: E-GEOD-59047 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.

Haverkamp Jessica M JM Smith Amber M AM Weinlich Ricardo R Dillon Christopher P CP Qualls Joseph E JE Neale Geoffrey G Koss Brian B Kim Young Y Bronte Vincenzo V Herold Marco J MJ Green Douglas R DR Opferman Joseph T JT Murray Peter J PJ

Immunity 20141211 6

Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting T cell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we found the monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-i ...[more]

PMID: 25500368

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Project description:Spinocerebellar Ataxia Type 2 (SCA2) is caused by expansion of a polyglutamine encoding triplet repeat in the human ATXN2 gene beyond (CAG)31. This is thought to mediate toxic gain-of-function by protein aggregation, and affect RNA processing, resulting in degenerative processes affecting preferentially cerebellar neurons. As a faithful animal model, we generated a knock-in mouse replacing the single CAG of murine Atxn2 with CAG42, a frequent patient genotype. This expansion size was inherited stably. The mice showed phenotypes with reduced weight and later motor incoordination. Although brain Atxn2 mRNA became elevated, soluble ATXN2 protein levels diminished over time, which might explain partial loss-of-function effects. Deficits in soluble ATXN2 protein correlated with the appearance of insoluble ATXN2, a progressive feature in cerebellum possibly reflecting toxic gains-of-function. Since in vitro ATXN2 overexpression was known to reduce levels of its protein interactor PABPC1, we studied expansion effects on PABPC1. In cortex, PABPC1 transcript, soluble and insoluble protein levels were increased. In more vulnerable cerebellum the progressive insolubility of PABPC1 was accompanied by decreased soluble protein levels, with PABPC1 mRNA showing no compensatory increase. The sequestration of PABPC1 into insolubility by ATXN2 function gains was validated in human cell culture. To understand consequences on mRNA processing, transcriptome profiles at medium and old age in three different tissues were studied and demonstrated selective induction of Fbxw8 in old cerebellum. Fbxw8 is encoded next to the Atxn2 locus and was shown in vitro to decrease the level of expanded insoluble ATXN2 protein. In conclusion, our data support the concept that expanded ATXN2 undergoes progressive insolubility and affects PABPC1 by a toxic gain-of-function mechanism with tissue-specific effects, which may be partially alleviated by the induction of FBXW8. Factorial design comparing Atxn2 knock-in mice with wild type littermates in three different tissues (brainstem, cerebellum, liver)

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Regulation of tumor associated macrophages by cooperative inflammatory signaling

Publications

Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways.

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