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Global genome expression analysis of lamina propria derived WT and Nlrp6-/- Ly6C-hi inflammatory monocytes

ABSTRACT: Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFα production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFα production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFα production in preventing chronic dysregulated inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE79631 | GEO | 2016/03/27

SECONDARY ACCESSION(S): PRJNA316515

REPOSITORIES: GEO

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Global genome expression analysis of lamina propria derived WT and Nlrp6-/- Ly6C-hi inflammatory monocytes

Project description:Nlrp6-/- lamina propria Ly6C-hi monocytes in response to AOM/DSS have deficient TNFÎ± production, but increased production of other pro-inflammatory cytokines as compared to WT NLRP6 is a member of the Nod-like receptor family, whose members are involved in the recognition of microbes and/or tissue injury. NLRP6 was previously demonstrated to regulate the production of IL-18 and is important for protecting mice against chemically-induced intestinal injury and colitis-associated colon cancer. However, the cellular mechanisms by which NLRP6 reduces susceptibility to colonic inflammation remain unclear. Here, we determined that NLRP6 expression is specifically upregulated in Ly6Chi inflammatory monocytes that infiltrate into the colon during dextran sulfate sodium (DSS)-induced inflammation. Adoptive transfer of WT Ly6Chi inflammatory monocytes into Nlrp6-/- mice was sufficient to protect them from mortality, significantly reducing intestinal permeability and damage. NLRP6-deficient inflammatory monocytes were specifically defective in TNFÎ± production, which was important for reducing DSS-induced mortality and dependent on autocrine IL-18 signaling by inflammatory monocytes. Our data reveal a previously unappreciated role for NLRP6 in inflammatory monocytes, which are recruited during intestinal injury to promote barrier function and limit bacteria-driven inflammation. This study also highlights the importance of early cytokine responses, particularly NLRP6-dependent and IL-18-dependent TNFÎ± production in preventing chronic dysregulated inflammation. Ly6Chi monocytes were sorted from lamina propria of WT or Nlrp6-/- mice at day 10 of AOM/2%DSS. RNA was extracted and hybridized to the mouse 2.1 ST array.

2016-03-27 | E-GEOD-79631 | biostudies-arrayexpress

Estrogen Receptor β Activation Inhibits Colitis by Promoting the NLRP6-Mediated Autophagy

Project description:Estrogen receptor β (ERβ) and NOD-, LRR- and pyrin domain-containing 6 (NLRP6) are highly expressed in intestinal tissues and reduce intestinal inflammation, but their underlying mechanisms are unclear. We found that ERβ and NLRP6 levels were reduced in patients with inflammatory bowel disease (IBD), and that deletion of ERβ or NLRP6 was exacerbated colitis in mouse models. We discovered that ERβ exerted its anti-inflammatory activity by inducing NLRP6-mediated autophagy. Specifically, ERβ directly regulated NLRP6 gene expression and NLRP6 inflammasome activation through genomic and non-genomic effects. NLRP6 directly interacted with multiple autophagy-related proteins (including ULK1, BECN1, ATG5-ATG12-ATG16L1 complex, p62, and PHB2). Autophagy stimulation suppresses the inflammatory response by eliminating excess ERβ, NLRP6, ASC, Casp-1, IL-1β, TNF-α and damaged mitochondria. These findings indicate that ERβ-NLRP6-autophagy forms a negative feedback loop to maintain intestinal epithelial cell homeostasis and facilitate tissue repair.

2023-06-05 | GSE151864 | GEO

TRIM33 deficiency in mature myeloid cells impairs resolution of colonic inflammation

Project description:Mature myeloid cells play a crucial role in the pathogenesis of Crohn disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. Here we show that Trim33 mRNA level is decreased in CD patient’s blood monocytes and characterize TRIM33 functions in monocytes during dextran sulfate sodium (DSS) induced colitis. Mice deleted for trim33 only in mature myeloid cells (Trim33-/- mice) display an impaired resolution of colonic inflammation. This deficiency is associated with an increased number of blood and colon neutrophils and monocytes and a decreased number of colonic macrophages. In accordance, Trim33-/- monocytes are less competent that wild type monocytes for recruitment and differentiation into macrophages at the inflammatory site. Furthermore, during resolution of DSS-induced colitis, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane bound TNFα known to regulate resolution of inflammation. Altogether, these results show an important role of TRIM33 in monocytes/macrophages during the resolution of DSS-induced colonic inflammation and pinpoint TRIM33 as a novel Crohn disease biomarker and as a potential therapeutic target.

2019-07-26 | GSE124778 | GEO

The role of methyl-CpG-binding domain protein-2 (MBD2) in colonic inflammation [series 2]

Project description:Mice deficient in MBD2 (Mbd2-/-) were treated with 2% dextran sulfate sodium or normal drinking water for 6 continuous days. A single cell suspension of colon lamina propria and epithelium was isolated, with monocytes (CD11b+ Ly6CHi, MHC-II+/-), macrophages (CD11b+ Ly6C-MHC-II+), cDC2s (CD11b- CD11c+ CD103+) and epithelial cells (CD45- EpCAM+) purified by FACS. Methyl-CpG-binding domain-2 (Mbd2) acts as an epigenetic regulator of gene expression, by linking DNA methylation to repressive chromatin structure. Although Mbd2 is widely expressed in gastrointestinal immune cells and is implicated in regulating intestinal cancer and anti-helminth responses, its role in controlling colitis has yet to be defined. Indeed, epigenetic control of gene expression in cells that regulate intestinal immunity is generally poorly understood, even though such mechanisms may explain the inability of standard genetic approaches to pinpoint the causes of conditions like inflammatory bowel disease. In this study we demonstrate a vital role for Mbd2 in regulating murine colonic inflammation. Mbd2-/- mice displayed dramatically worse pathology than wild type controls during dextran sulphate sodium (DSS) induced colitis, with increased inflammatory (IL-1β+) monocytes. Profiling of mRNA from innate immune and epithelial cell (EC) populations suggested that Mbd2 suppresses inflammation and pathology via control of innate-epithelial cell crosstalk and T cell recruitment. Consequently, restriction of Mbd2 deficiency to CD11c+ dendritic cells and macrophages, or to ECs, resulted in increased DSS colitis severity. Our identification of this dual role for Mbd2 in regulating the inflammatory capacity of both CD11c+ cells and ECs highlights how epigenetic control mechanisms may limit intestinal inflammatory responses.

2020-02-26 | GSE134281 | GEO

The role of methyl-CpG-binding domain protein-2 (MBD2) in colonic inflammation [series 1]

2020-02-26 | GSE134280 | GEO

NanoString nCounter immune-related gene expression in blood sorted CD14+CD16- monocytes from sALS, fALS and HC subjects

Project description:We investigated the innate immune system in the SOD1 ALS model. We found that splenic Ly6CHi monocytes were activated and their progressive recruitment to the spinal cord, but not brain, correlated with neuronal loss. We found a decrease in resident microglia in the spinal cord with disease progression. Two months prior to disease onset, splenic Ly6CHi monocytes had an M1 signature which included increased CCR2. At one month prior to disease onset, microglia expressed increased CCL2 and other chemotaxis-associated molecules. Microglia derived from the spinal cord of SOD1 mice recruited Ly6C+ monocytes to the CNS. Treatment with anti-Ly6C mAb modulated the Ly6CHi monocyte cytokine profile, reduced monocyte recruitment to the spinal cord, diminished neuronal loss and extended survival. In humans with ALS, CD14+/CD16- monocytes (analogue of Ly6CHi monocytes) exhibited an ALS specific microRNA inflammatory signature similar to that observed in the SOD1 mouse providing a direct link between the animal model and the human disease. Thus, the SOD1-like profile of monocytes in ALS subjects may serve as a biomarker for disease stage or progression. Our results suggest that recruitment of inflammatory monocytes plays an important role in disease progression and that modulation of these cells is a potential therapeutic approach This study used the NanoString nCounter hybridization system and the Nanostring GX Human Immunology and Nanostring Human Inflammation assays to identify and quantitate immune-related genes in blood CD14+CD16- monocytes from ALS, MS and HC subjects Total RNA was isolated from FACS sorted CD14+CD16- blood-derived monocytes from sporadic sALS (n=10), fALS (n=4) and HC (n=10) subjects. RNA was profiled using the Nanostring GX Human Immunology and Nanostring Human Inflammation assays

2012-07-25 | E-GEOD-39642 | biostudies-arrayexpress

Genome-wide analysis of tissue-specific gene expression by Ly6Chi inflammatory monocytes during Toxoplasma gondii infection

Project description:Analysis of Ly6Chi monocytes from small intestine lamina propria (SILP) and blood of day 8 Toxoplasma gondii infected mice at gene expression level. The hypothesis tested in the present study was that Ly6Chi monocytes from SILP have altered expression of regulatory factors to blood monocytes. Results provide important information on the regulatory to effector balance of genes expressed by Ly6Chi monocytes during an acute inflammatory response. Ly6Chi inflammatory monocytes were sorted by FACS from the blood or small intestine lamina propria (SILP) of Toxoplasma gondii infected C57BL/6 mice. Cells were isolated at day 8 after infection and total RNA obtained from sorted populations. Three biological replicates were acquired for both blood and SILP from pooled animals.

2013-05-25 | E-GEOD-46685 | biostudies-arrayexpress

Notch and TLR signaling coordinate monocyte cell fate and inflammation

Project description:We studied the role of Notch2 signaling in Ly6Chi monocyte cell fate during TLR7-induced acute inflammation. To characterize the gene expression changes involved in monocyte differentiation, we subjected monocyte subsets from peripheral blood of wt and myeloid Notch2 mutant mice after Sham or IMQ treatment to RNA-sequencing and gene expression analysis. We found that Cell-intrinsic Notch2 and TLR7-Myd88 pathways independently and synergistically promote Ly6Clo patrolling monocyte development from Ly6Chi monocytes under inflammatory conditions. At the same time TLR7 stimulation in the absence of functional Notch2 signaling promotes resident tissue macrophage gene expression signatures in monocytes and ectopic differentiation of Ly6Chi monocytes into macrophages and dendritic cells. Thus, Notch2 is a master regulator of Ly6Chi monocyte cell fate and inflammation in response to TLR signaling.

2020-08-04 | GSE147492 | GEO

RNA sequencing of FHR1-treated human monocytes

Project description:The plasma protein FHR1 induces release of inflammatory cytokines IL-1β, IL-6, IL-18 or TNFα from blood-derived human monocytes. RNA sequencing was performed from RNA of BSA- or FHR1-treated monocytes from 4 different donors. In response to FHR1, 522 monocytic genes were upregulated (gene ontology enrichment analysis), including 35 inflammation related genes, e.g. TNF. Also, G protein-coupled receptors such as EMR2/ADGRE2 were upregulated in response to FHR1.

2018-08-25 | GSE119025 | GEO

Control of intestinal homeostasis, colitis and colitis-associated colorectal cancer by the inflammatory caspases

Project description:Inflammatory caspases are essential effectors of inflammation and cell death. Here, we investigated their roles in colitis and colorectal cancer and report a bimodal regulation of intestinal homeostasis, inflammation and tumorigenesis by caspases-1 and -12. Casp1-/- mice exhibited defects in mucosal tissue repair and succumbed rapidly after dextran sulfate sodium (DSS) administration. This phenotype was rescued by administration of exogenous interleukin-18 and was partially reproduced in mice deficient in the inflammasome adaptor ASC. Casp12-/- mice, in which the inflammasome is derepressed, were resistant to acute colitis and showed signs of enhanced repair. Together with their increased inflammatory response, the enhanced repair response of Casp12-/- mice rendered them more susceptible to colorectal cancer induced by azoxymethane (AOM)+DSS. Taken together, our results indicate that the inflammatory caspases are critical in the induction of inflammation in the gut following injury, which is necessary for tissue repair and maintenance of immune tolerance. Total RNA obtained from isolated tumors or normal colon tissue from wild type and caspase-12 deficient mice were compared.

2010-07-30 | E-GEOD-20407 | biostudies-arrayexpress

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