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Pulmonary interstitial macrophages are required to mediate the pro-tumorigenic effects of IL-9

ABSTRACT: We demonstrate that deficiency of IL-9 signaling inhibits lung tumor growth in multiple models. In defining the IL-9-responsive cells in the lung tumor models, we found IL-9 regulates lung heterogeneity by inhibiting alveolar macrophage and promoting the expansion of both CD11c+ and CD11c- interstitial macrophage populations. Interstitial macrophages are a critical IL-9-responsive population that is required to promote lung tumor growth. Mechanistically, the IL-9/macrophage axis requires arginase1 (Arg1) to mediate tumor growth. Adoptive transfer of Arg1+ but not Arg1- lung macrophages to Il9r-/- mice dramatically increases the tumor growth. In parallel, the elevated expression of IL-9R and Arg1 in human tumor associated macrophages is correlated with poor prognosis among lung cancer patients. Moreover, targeting IL-9 signaling in lung macrophages limited lung tumor growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE174005 | GEO | 2022/01/03

REPOSITORIES: GEO

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An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment

Project description:Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9 responsive cell repertoire is still not well defined. Here, we found IL-9 mediates pro-allergic activities by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+/- interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affects the function of lung macrophages by inducing Arg1 activity. Compared to Arg1-deficient lung macrophages, Arg1-expressing macrophages co-express greater amounts of CCL5. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages can recover allergic inflammation that is lost in Il9r-/- mice. In parallel, the elevated expression of IL-9, IL-9R, Arg1 and CCL5 is correlated with disease in asthma patients. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation.

2021-11-15 | GSE162898 | GEO

Microarray analysis of brain macrophage subsets and peripheral blood monocytes in traumatic brain injury

Project description:We compared arginase-1+ macrophages (macrophages were defined by flow cytometry as CD45hi CD11b+ Ly6G-) with arginase-1- brain macrophages following traumatic brain injury (TBI) by isolating these cells from YARG transgenic mice, which express YFP under the arginase-1 promoter. Both cell populations were isolated from YARG brain tissues one day following TBI. We also examined the expression profile of peripheral blood monocytes (monocytes were defined by flow cytometry as CD11bhi F4/80+) from injured YARG mice and from normal YARG mice. Peripheral blood samples were compared to TBI brain macrophages to assess gene expression changes before and after infiltration into the brain. TBI macrophage subsets were identified by using a reporter mouse strain (YARG) that expresses eYFP from an IRES inserted at the 3' end of the gene for arginase-1 (Arg1), a hallmark of alternatively activated (M2) macrophages. One day after TBI, 21Â±1.5% of ipsilateral brain macrophages expressed relatively high levels of Arg1 as detected by YFP. Gene expression analysis of Arg1+ and Arg1- brain macrophage populations revealed that these populations were distinct from either classically activated (M1) macrophages or M2 macrophages, with features of both. The Arg1+ cells differed from Arg1- cells in multiple aspects, most notably in their chemokine repertoires. Thus, the macrophage response to TBI involves recruitment of at least two major macrophage subsets. Overall, our data indicate that the macrophage response to TBI is heterogeneous and unique. Four groups (Arg1- brain macrophages post-TBI, Arg1+ brain macrophages post-TBI, normal blood monocytes, blood monocytes post-TBI) were analyzed. Four replicates of each group were analyzed for a total of 16 samples (only 3 replicates of the blood monocyte groups are included in this submission).

2013-05-01 | E-GEOD-39759 | biostudies-arrayexpress

The immunomodulatory effects of periostin on monocyte-derived macrophages

Project description:To explore the effects of periostin on tumor-associated macrophagess, we first sorted CD14+ monocytes from peripheral blood mononuclear cells of healthy donors using magnetic-activated cell sorting and then induced their differentiation into macrophages by culture with M-CSF for 5 days. In the absence of IL-4 stimulation, these macrophages expressed CD163 and Arg1 (a marker of M2 macrophage activation) but not CD206, suggesting that they were similar to macrophages in the early stage of mycosis fungoides (low frequency of CD206+ cells and low IL-4 expression). We then stimulated these macrophages with or without 100 ng/ml of periostin for 6 hours and examined gene expression using a cDNA microarray. Periostin stimulated gene expression on monocyte-derived macrophages was measured at 6 hours after exposure to doses of 100 ng/ml periostin.

2015-07-14 | E-GEOD-70821 | biostudies-arrayexpress

Arginine utilization following mycobacteria infection in macrophages is dependent on autocrine-paracrine signaling

Project description:Nitric oxide (NO) produced by macrophages (MØs) is toxic to both host tissues and invading pathogens and its regulation is therefore essential to suppress host cytotoxicity. MØ arginase 1 (Arg1) inhibits NO production by competing with NO synthases for arginine, the common substrate of NO synthases and arginases. Two signal transduction pathways control Arg1 expression in MØs. First, a MyD88-dependent pathway induces Arg1 in intracellular infections, while a second Stat6-dependent pathway is required for Arg1 expression in alternativelyactivated MØs. We found that mycobacteria-infected MØs produce soluble factors that induce Arg1 in an autocrine-paracrine manner via Stat3. We identify these factors as IL-6, IL-10 and GCSF. We further establish that Arg1 expression is controlled by the MyD88-dependent production of IL-6, IL-10 and G-CSF rather than cell intrinsic MyD88 signaling to Arg1. Our data reveal the MyD88-dependent pathway of Arg1induction following BCG infection requires Stat3 activation and may result in the development of an immunosuppressive niche in granulomas due to the induced Arg1 production in surrounding uninfected MØs We used microarrays to perform genome wide expression analysis in mycobacteria-infected macrophages from C57Bl/6 WT and MyD88-knockout mice.

2010-07-14 | E-GEOD-22935 | biostudies-arrayexpress

Super-paramagnetic iron oxide nanoparticles reprogram the tumor microenvironment and reduce lung cancer growth

Project description:Tumor associated macrophages (TAMs) are known to play a role in a multitude of processes that facilitate lung cancer growth, including the suppression of tumoricidal immune activation and the absorption of chemotherapeutics. Therefore, deciphering new therapies to reprogram TAMs towards an anti-tumor phenotype is at the cutting-edge of therapy development. The presence of iron-loaded macrophages has been associated with a better prognosis in lung cancer patients. Iron accumulation in macrophages stimulates pro-tumoricidal macrophage activity that triggers cytotoxic T-cell responses in the tumor microenvironment. In this study, we propose super-paramagnetic iron oxide nanoparticles (SPIONs) as a promising anti-lung cancer adjuvant therapy to reduce tumor cell growth. We used SPIONs to target iron to macrophages and observed that SPION-loaded macrophages reduced tumor cell growth due to the oxidative stress. Additionally, we found that SPIONs completely rewire the tumor microenvironment in mice towards an anti-tumor state and that in combination with crizotinib, a lung cancer targeted therapy, SPIONs show an additive effect in decelerating tumor growth

2024-04-18 | PXD040145 | Pride

Bone marrow LysM-Cre mediated TFEB overexpression significantly affected the response of bone marrow-derived macrophages to tumor material, decreasing both the expression of typical M2-like macrophage associated genes and inflammatory response genes.

Project description:In order to examine the effects of TFEB overexpression in macrophages on anti-tumor immunity, 8 week-old, female LysM-Double-Cre x TFEB transgene+ (TFEBtg) and LysM-Double-Cre x TFEB transgene- (WT) mice were sacrificed and their bone marrow was differentiated into macrophages using recombinant M-CSF. After one week of differentiation, macrophages were replated and treated with either DMEM only or DMEM supplemented with tumor-conditioned medium (serum-free DMEM supernatant exposed to EO771 tumor cells) and tumor lysate for 24 hours. Macrophages were then collected and gene expression was analyzed using whole genome microarray. TFEBtg macrophages expressed significantly less typical M2-like macrophage genes, such as Arg1 and IL-10, than WT macrophages when exposed to tumor-conditioned medium and lysate. TFEB overexpression also decreased the expression of pro-inflammatory genes such as IL-1β, IL-6, and NLRP3 as well as genes involved in PGE2 synthesis, such as COX2, HIF-1α, MIF, and cPLA2. RT-qPCR was used to confirm the expression of the genes listed and many others. Ingenuity Pathway Analysis was also performed in order to analyze the expression of genes clustered by functional relationships. Mice treated to increase TFEB expression demonstrated decreased breast tumor growth.

2020-03-31 | GSE139554 | GEO

CD11c+ macrophages are pro-angiogenic and necessary for experimental choroidal neovascularization

Project description:Patients with neovascular AMD (nAMD) suffer vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Macrophages are found in CNV lesions from nAMD patients. Additionally, Ccr2-/- mice, which lack classical monocyte-derived macrophages, show reduced CNV size. However, macrophages are highly diverse cells that can perform multiple functions. We performed single-cell RNA-sequencing on immune cells from wildtype and Ccr2-/- eyes to uncover macrophage heterogeneity during the laser-induced CNV mouse model of nAMD. We identified 12 macrophage subtypes, including Spp1+ macrophages. Spp1+ macrophages were enriched from wildtype lasered eyes and expressed a pro-angiogenic transcriptome via multiple pathways, including vascular endothelial growth factor signaling, endothelial cell sprouting, cytokine signaling, and fibrosis. Additionally, Spp1+ macrophages expressed the marker CD11c, and CD11c+ macrophages were increased by laser and present in CNV lesions. Finally, CD11c+ macrophage depletion reduced CNV size by 40%. These findings broaden our understanding of ocular macrophage heterogeneity and implicate CD11c+ macrophages as a potential therapeutic target for treatment-resistant nAMD patients.

2023-02-27 | GSE222094 | GEO

The immunomodulatory effects of periostin on monocyte-derived macrophages

2015-07-14 | GSE70821 | GEO

Gene network analysis of interstitial macrophages after treatment with induced pluripotent stem cells secretome (iPSC-cm) in the bleomycin injured rat lung

Project description:Idiopathic pulmonary fibrosis (IPF) is a complex disease involving various cell types. Macrophages are essential in maintenance of physiological homeostasis, wound repair and fibrosis in the lung. Macrophages play a crucial role in repair and remodeling by altering their phenotype and secretory pattern in response to injury. The secretome of induced pluripotent stem cells (iPSC-cm) attenuates injury and fibrosis in bleomycin injured rat lungs. In the current study, we evaluate the effect of iPSC-cm on interstitial macrophage gene expression and phenotype in bleomycin injured rat lungs in vivo. Â iPSC-cm was intratracheally instilled 7 days after bleomycin induced lung injury and assessed 7 days later and single cell isolation was performed. Macrophages were FACS sorted and microarray analysis was performed. We characterized changes in the rat lung interstitial macrophages using transcriptional profiling.

2017-03-20 | E-MTAB-5619 | biostudies-arrayexpress

Transcriptomic profiling of lung monocytes and macrophages in mice

Project description:We developed a simplified flow cytometry strategy in order to discriminate monocytes and macrophages in the lung of C57BL/6 mice. Using this strategy, we identified autofluorescent F4/80+ CD11c+ alveolar macrophages, non-autofluorescent CD64+Ly-6C- interstitial macrophages and Ly-6Chi monocytes residing in the lung of WT mice. A fraction of these Ly-6Chi monocytes corresponded to classical blood monocytes associated with the lung vasculature, but another fraction did not depend on CCR2, the chemokine receptor required for monocytes to egress from the bone marrow, as a population of lung Ly-6Chi monocytes was also present in the lung of Ccr2-/- mice. A remaining question was whether lung monocytes represented a particular population of monocytes that could be distinguishable from the classical CCR2-dependent blood monocytes. To address this issue, we performed a transcriptomic comparison of Ly-6Chi monocytes recovered from flushed lung of WT mice (â60% of CCR2- dependent classical blood monocytes and â40% of lung monocytes) and Ccr2-/- mice (more than 95% of lung monocytes). In addition, we tested whether exposure to TLR ligands would affect interstitial macrophages, and we compared to transcriptome of IM at steady-state and IM 1 week after administration of 50 Âµg CpG-DNA intratracheally.

2017-03-01 | E-MTAB-5012 | biostudies-arrayexpress

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