Inflammatory monocytes promote granuloma control of Yersinia infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA800334 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17734386.fastq.gz | Fastqsanger.gz | |||
| SRR17734387.fastq.gz | Fastqsanger.gz | |||
| SRR17734388.fastq.gz | Fastqsanger.gz | |||
| SRR17734389.fastq.gz | Fastqsanger.gz | |||
| SRR17734390.fastq.gz | Fastqsanger.gz |
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Project description:Granulomas are organized immune cell aggregates formed in response to chronic infection or antigen persistence. The bacterial pathogen Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signalling and immune defence, inducing neutrophil-rich pyogranulomas (PGs) within lymphoid tissues. Here we uncover that Yp also triggers PG formation within the murine intestinal mucosa. Mice lacking circulating monocytes fail to form defined PGs, have defects in neutrophil activation and succumb to Yp infection. Yersinia lacking virulence factors that target actin polymerization to block phagocytosis and reactive oxygen burst do not induce PGs, indicating that intestinal PGs form in response to Yp disruption of cytoskeletal dynamics. Notably, mutation of the virulence factor YopH restores PG formation and control of Yp in mice lacking circulating monocytes, demonstrating that monocytes override YopH-dependent blockade of innate immune defence. This work reveals an unappreciated site of Yersinia intestinal invasion and defines host and pathogen drivers of intestinal granuloma formation.
2022-02-07 | GSE194334 | GEO
Project description:Granulomas are organized immune cell aggregates formed in response to chronic infection or antigen persistence. The bacterial pathogen Yersinia pseudotuberculosis (Yp) blocks innate inflammatory signalling and immune defence, inducing neutrophil-rich pyogranulomas (PGs) within lymphoid tissues. Here we uncover that Yp also triggers PG formation within the murine intestinal mucosa. Mice lacking circulating monocytes fail to form defined PGs, have defects in neutrophil activation and succumb to Yp infection. Yersinia lacking virulence factors that target actin polymerization to block phagocytosis and reactive oxygen burst do not induce PGs, indicating that intestinal PGs form in response to Yp disruption of cytoskeletal dynamics. Notably, mutation of the virulence factor YopH restores PG formation and control of Yp in mice lacking circulating monocytes, demonstrating that monocytes override YopH-dependent blockade of innate immune defence. This work reveals an unappreciated site of Yersinia intestinal invasion and defines host and pathogen drivers of intestinal granuloma formation.
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Project description:Disease tolerance is an important alternative strategy for rapidly acquired immunity to malaria. We show that tolerance is induced by a single malaria episode - in the absence of parasite clearance. Inflammatory spleen monocytes from C57Bl6/J mice respond with interferon-stimulated inflammation to acute first Plasmodium chabaudi infection and are destined to differentiate into inflammatory macrophages. This dramatic transcriptional response is tolerised during persisting chronic infection (with parasite densities up to 1000 parasites per µl), since the fitness costs of maintaining an emergency inflammatory response for several months would not be compatible with survival. However, spleen monocytes from chronically infected mice are not in a permanent refractory state, since their inflammatory response is identical to monocytes from uninfected mice when removed from the spleen and stimulated with LPS in vitro. Using a newly developed reinfection model to closely match parasitaemia between first and second P. chabaudi infection, we further uncover that memory of first malaria infection (30 days after drug treatment of chronic infection) dramatically changes the transcriptional response of inflammatory spleen monocytes to second infection. They now minimise inflammation and instead promote stress and tissue tolerance. This unique functional profile is not underpinned by alterations in the epigenetic landscape of inflammatory monocytes before their release from the bone marrow (link to GEO ChIPseq) - tolerance is therefore imprinted within the spleen. Hosts thus acquire long-lasting mechanisms that control inflammation (reducing collateral tissue damage) and learn to actively promote stress tolerance (protecting tissues against toxic products and processes) after one malaria episode.
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Project description: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. 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.
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Project description:Calcific Aortic Valve Disease (CAVD) is the most frequent valvular heart disease in developed countries. It is characterized by a progressive calcification of aortic valve leaflets mediated by myeloid cells, such as monocytes and macrophages. However, the molecular mechanisms involved in their recruitment and activity are still poorly understood and limit the development of a pharmacological treatments. Previous studies have already demonstrated the role of macrophages in CAVD development. However, little is known about the implication of their precursors, monocytes. Thus, we hypothesized that circulating monocytes from CAVD patients have higher pro-calcific and pro-inflammatory capacities. We aimed first to assess the pro-calcifying potential of circulating monocytes from patients with CAVD and second to better understand the molecular mechanisms of this pro-calcific effect through a whole transcriptomic study. Methods : We first characterized monocytes sub-population, from PBMCs isolated from peripheral blood of healthy volunteers (Vol) and patients with CAVD or without CAVD (NCAVD), with flow cytometry. Then we analyzed the whole transcriptome of these monocytes by RNA sequencing (RNAseq) to identify dysregulated genes expression, further confirmed by RT-qPCR. Finally, after evaluation of monocytes secretome with multiplex analysis, we evaluated CAVD monocytes capacities to induce myofibroblastic transdifferenciation and osteoblastic differencitation of human valvular interstitial cells (hVIC) with immunocytochemistry (ICC) and O-cresolphtalein assay. Results : In CAVD (calcific aortic valve disease) monocytes, we observe a shift in their sub-populations, with an increased frequency of classical monocytes (CD14+CD16-) and a decreased frequency of non-classical monocytes (CD14+CD16++). Interestingly, we found specific upregulation of genes linked to both inflammation (PDK4) and calcification (ATP2B1), alongside the downregulation of immunomodulatory genes (DDR1, IKBKE) in monocytes from CAVD patients. Additionally, CAVD monocytes produce lower levels of immunomodulatory and anti-osteoblastogenic cytokines (IL3, CCL3), which promote myofibroblastic transdifferentiation (TIMP1, TNC) and osteoblastic differentiation (ALPL, OPG). This correlates with an increase in αsma+ and opn+ cells and a doubling of hVIC calcifications. Conclusions : We demonstrated for the first time that circulating monocytes from CAVD patients have higher pro-inflammatory and pro-calcific capacities that might promote CAVD development. Likewise, we identify dysregulated genes, which could be used as new therapeutic targets.
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Project description:Co-culture of platelets with monocytes induces the forming of multinucleated giant foam cells (MP-Mac or MP-MNGCs). Compared with normal monocyte differentiated macrophages (M-Mac), the MP-MNGCs can engulf more mycobacteria with suppressed inflammatory responses (releasing more IL-10 with less TNF-gamma). Microarray analysis demonstrated that the MP-MNGCs greatly up-regulated CXCL5, PPBP, NT5E, PDPN, CXCL3 and other M2 related genes, such as ARG1, CXCL1, CD163, etc. GO analysis revealed higher cluster of genes in response to wounding and nuclear division. Immunohistochemistry studies indicated similar high expression of IL-10, CXCL5, CXCL3, PDPN and ARG1 expression in MNGCs of TB granuloma, which indicated that phagocytosis of activated platelets by monocytes might be involved in pathogenesis of TB granuloma.
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