Dataset Information

Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases.

ABSTRACT: Background: Metastatic breast cancer cells recruit macrophages (metastasis-associated macrophages, or MAMs) to facilitate their seeding, survival and outgrowth. However, a comprehensive understanding of the gene expression program in MAMs and how this program contributes to metastasis remain elusive. Methods: We compared the transcriptomes of MAMs recruited to lung metastases and resident alveolar macrophages (RAMs) and identified a large variety of differentially expressed genes and their associated signaling pathways. Some of the changes were validated using qRT-PCR and immunofluorescence. To probe the functional relevance to metastatic growth, a gene-targeting mouse model of female mice in the C57BL6/J background was used to study allograft inflammatory factor 1 (AIF1, also known as ionized calcium-binding adapter molecule 1 or IBA1). Results: Interferon signaling is one of the most activated pathways in MAMs, with strong upregulation of multiple components of the pathway and a significant enrichment for the gene signatures of interferon-alpha-treated human macrophages. Aif1, an interferon-responsive gene that regulates multiple macrophage activities, was robustly induced in MAMs. Aif1 deficiency in MAMs, however, did not affect development of lung metastases, suggesting that AIF1 indicates MAM activation but is dispensable for regulating metastasis. Conclusions: The drastically different gene expression profile of MAMs as compared to RAMs suggests an important role in promoting metastatic growth. Dissection of the underlying mechanisms and functional validation of potential targets in the profile may provide novel therapeutic strategies for the treatment of metastatic diseases.

SUBMITTER: Zheng W

PROVIDER: S-EPMC8008350 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundKawasaki disease (KD) is widely viewed as an acute arteritis. However, our pathologic studies show that chronic coronary arteritis can persist long after disease onset and is closely linked with arterial stenosis. Transcriptome profiling of acute KD arteritis tissues revealed upregulation of T lymphocyte, type I interferon, and allograft inflammatory factor-1 (AIF1) genes. We determined whether these immune responses persist in chronic KD arteritis, and we investigated the role of AIF1 in these responses.MethodsGene expression in chronic KD and childhood control arteries was determined by real-time reverse-transcriptase polymerase chain reaction, and arterial protein expression was determined by immunohistochemistry and immunofluorescence. Allograft inflammatory factor-1 small-interfering ribonucleic acid macrophage treatment was performed to investigate the role of AIF1 in macrophage and T lymphocyte activation.ResultsAllograft inflammatory factor-1 protein was highly expressed in stenotic KD arteries and colocalized with the macrophage marker CD68. T lymphocyte and interferon pathway genes were significantly upregulated in chronic KD coronary artery tissues. Alpha interferon-induced macrophage expression of CD80 and major histocompatibility complex class II was dependent on AIF1, and macrophage expression of AIF1 was required for antigen-specific T lymphocyte activation.ConclusionsAllograft inflammatory factor-1, originally identified in posttransplant arterial stenosis, is markedly upregulated in KD stenotic arterial tissues. T lymphocyte and type I interferon responses persist in chronic KD arteritis. Allograft inflammatory factor-1 may play multiple roles linking type I interferon response, macrophage activation, and antigen-specific T lymphocyte activation. These results suggest the likely importance of lymphocyte-myeloid cell cross-talk in the pathogenesis of KD arteritis and can inform selection of new immunotherapies for clinical trials in high-risk KD children.

Project description:Interleukin (IL)-33 is an interleukin-1 like cytokine that enhances Th2 responses and mediates mucosal immunity and allergic inflammation but the mechanism regulating endogenous IL-33 production are still under investigation. In macrophages, lipopolysaccharide (LPS) administration resulted in marked induction of IL-33 mRNA that was blunted in macrophages from glutaredoxin-1 (Glrx) knockout mice and in RAW264.7 macrophages with Glrx knockdown by siRNA. Glutaredoxin-1 is a small cytosolic thioltransferase that controls a reversible protein thiol modification, S-glutationylation (protein-GSH adducts), thereby regulating redox signaling. In this study, we examined the mechanism of Glrx regulation of endogenous IL-33 induction in macrophages. Glrx knockdown resulted in impaired de-glutathionylation of TRAF6, which is required for TRAF6 activation, and inhibited downstream IKK? and NF-?B activation. Inhibitors of NF-?B suppressed IL-33 induction and chromatin IP sequencing data analysis confirmed that IL-33 is an NF-?B-responsive gene. Since TRAF6-NF-?B activation is also essential for IL-33 signaling through its receptor, ST2L, we next tested the involvement of Glrx in exogenous IL-33 responses in RAW264.7 cells. Recombinant IL-33 (rIL-33) administration induced IL-33 mRNA expression in RAW264.7 macrophages, and this was inhibited by Glrx knockdown. Interestingly, rIL-33-induced IL-33 protein was identified as the 20 kDa cleaved form whereas LPS-induced IL-33 protein was identified as full-length IL-33, which may be less active than the cleaved form. In a clinically-relevant mouse model of asthma, intra-tracheal cockroach antigen treatment induced Glrx protein in wild type mouse lungs but Glrx induction was attenuated in IL-33 knockout mouse lungs, suggesting that IL-33 may regulate Glrx induction in vivo in response to allergen challenge. In summary, our data reveal a novel mechanism by which Glrx controls both LPS- and IL-33-mediated NF-?B activation leading to IL-33 production, and paracrine IL-33 can induce Glrx to further regulate inflammatory reactions.

Dataset Information

Induction of interferon signaling and allograft inflammatory factor 1 in macrophages in a mouse model of breast cancer metastases.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets