Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis III
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ABSTRACT:
PROVIDER: PRJNA1181889 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31221476_1.fastq.gz | Fastqsanger.gz | |||
| SRR31221476_2.fastq.gz | Fastqsanger.gz | |||
| SRR31221477_1.fastq.gz | Fastqsanger.gz | |||
| SRR31221477_2.fastq.gz | Fastqsanger.gz | |||
| SRR31221478_1.fastq.gz | Fastqsanger.gz |
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Project description:The macrophage response to infected microbes is crucial for the development of life-threatening sepsis. However, the mechanisms underlying pathophysiological regulation of macrophage subsets during sepsis remain poorly understood. Here, we report a novel mechanism in which the adhesion and degranulation-promoting adapter protein (ADAP) is essential for priming macrophages to induce podoplanin (PDPN) in response to bacterial infection during sepsis. We showed that ADAP expression was robustly induced in macrophages following LPS stimulation and was associated with sepsis severity. Furthermore, PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a novel mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.
2025-01-10 | GSE281052 | GEO
Project description:The macrophage response to infected microbes is crucial for the development of life-threatening sepsis. However, the mechanisms underlying pathophysiological regulation of macrophage subsets during sepsis remain poorly understood. Here, we report a novel mechanism in which the adhesion and degranulation-promoting adapter protein (ADAP) is essential for priming macrophages to induce podoplanin (PDPN) in response to bacterial infection during sepsis. We showed that ADAP expression was robustly induced in macrophages following LPS stimulation and was associated with sepsis severity. Furthermore, PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a novel mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.
2025-01-10 | GSE281047 | GEO
Project description:The macrophage response to infected microbes is crucial for the development of life-threatening sepsis. However, the mechanisms underlying pathophysiological regulation of macrophage subsets during sepsis remain poorly understood. Here, we report a novel mechanism in which the adhesion and degranulation-promoting adapter protein (ADAP) is essential for priming macrophages to induce podoplanin (PDPN) in response to bacterial infection during sepsis. We showed that ADAP expression was robustly induced in macrophages following LPS stimulation and was associated with sepsis severity. Furthermore, PDPN failed to be upregulated in TLR4 stimulated macrophages deficient in ADAP. A distinct PDPNhi peritoneal macrophage (PM) subset, which exhibited an M2-like phenotype and enhanced phagocytic activity, was generated in WT but not in ADAP-deficient septic mice. The blockade of PDPNhi PMs mimicked the effect of ADAP deficiency, which exacerbated sepsis. Mechanistically, BTK-mediated ADAP Y571 phosphorylation worked together with mTOR to converge on STAT3 activation for the transactivation of the PDPN promoter. Moreover, agonist activation of STAT3 profoundly potentiated the PDPNhi PM subset generation and alleviated sepsis severity in mice. Together, our findings reveal a novel mechanism whereby ADAP resets macrophage function by controlling the TLR4-induced upregulation of PDPN as a host innate immune defense during sepsis.
2025-01-10 | GSE281049 | GEO
Project description:Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis
| PRJNA1181884 | ENA
Project description:Molecular control of PDPNhi macrophage subset induction by ADAP as a host defense in sepsis II
| PRJNA1181887 | ENA
Project description:Heightened platelet phagocytosis by macrophages accompanied with an increase in IFN-γ is often attributed to the etiology of immune thrombocytopenia (ITP), an autoimmune disease characterized by low platelet counts. While deletion of the hematopoietic cell adaptor protein ADAP predisposes to ITP in mice, the mechanisms that underlie the functional role of ADAP during ITP remains largely unknown. Here we report that ADAP restrains platelet clearance by macrophages via modulation of STAT1-FcγR signaling axis. We show that under-expression of ADAP in splenic macrophage was associated with low platelet counts in patients with ITP. Further, macrophages from Adap−/− mice had an elevated phagocytosis capacity and exhibited upregulated pro-inflammatory signaling, and the thrombocytopenia in Adap−/− mice was mitigated in vivo by depletion of macrophages. Mechanically, ADAP interacted and competed with STAT1 binding to importin a5, a nuclear shuttling receptor for activated STAT1. While having no effect on STAT1 tyrosine phosphorylation, loss of ADAP increased the assembly of STAT1-importin a5 complex and facilitated STAT1 nuclear entry, leading to a selective enhancement of transcription of FcγRI/IV in macrophages. Moreover, pharmacological inhibition of STAT1 or disruption of STAT1-importin a5 interaction relieved the thrombocytopenia in Adap−/− mice. Thus, our findings reveal a critical role for ADAP as an intracellular immune checkpoint for shaping macrophage phagocytic ability in homeostatic maintenance of platelets.
2022-06-21 | GSE183385 | GEO
Project description:The adhesion and degranulation-promoting adaptor protein (ADAP) serves as a multifunctional scaffold and is involved in the formation of immune signaling complexes. To date only limited data exist regarding the role of ADAP in pathogen-specific immunity during in vivo infection and its contribution in phagocyte-mediated antibacterial immunity remains elusive. Here we show that mice lacking ADAP (ADAPko) are highly susceptible to the infection with the intracellular pathogen Listeria monocytogenes (Lm) by showing enhanced immunopathology in infected tissues together with increased morbidity, mortality and excessive infiltration of neutrophils and inflammatory monocytes. Despite high phagocyte numbers in spleen and liver, ADAPko mice only inefficiently controlled pathogen growth hinting at a functional impairment of infection-primed phagocytes in the ADAP-deficient host. Flow cytometric analysis of hallmark pro-inflammatory mediators and unbiased whole genome transcriptional profiling of neutrophils and inflammatory monocytes uncovered broad molecular alterations in the inflammatory program in both phagocyte subsets following their activation in the ADAP-deficient host. Strikingly, ex vivo phagocytosis assay revealed impaired phagocytic capacity of neutrophils, and, inflammatory monocytes derived from Lm-infected ADAPko mice. Together, our data suggest that an alternative priming of phagocytes in ADAP-deficient mice during Lm infection induces marked alterations in the inflammatory profile of neutrophils and inflammatory monocytes that contribute to enhanced immunopathology while limiting their capacity to eliminate the pathogen and to prevent the fatal outcome of the infection.
2021-10-20 | GSE175993 | GEO
Project description:is involved in the formation of immune signaling complexes. To date only limited and moreover 35 conflicting data exist regarding the role of ADAP in NK cells. To extend existing knowledge we 36 investigated ADAP-dependency of NK cells in the context of in vivo infection with the intracellular 37 pathogen Listeria monocytogenes (Lm). Ex vivo analysis of infection-primed NK cells revealed 38 impaired expression of IFN-γ and chemokines as well as impaired cytotoxic capacity in NK cells 39 lacking ADAP as indicated by reduced CD107a surface expression and inefficient perforin 40 production. However, ADAP-deficiency had no global effect on NK cell morphology or intracellular 41 distribution of CD107a-containing vesicles. Proteomic definition of ADAPko and wild type NK cells 42 did not uncover obvious differences in protein composition during the steady state and moreover, 43 similar early response patterns were induced in NK cells upon infection independent of the genotype. 44 In line with protein network analyses that suggested an altered migration phenotype in naïve 45 ADAPko NK cells, in vitro migration assays uncovered significantly reduced migration of both naïve 46 as well as infection-primed ADAPko NK cells compared to wild type NK cells. We propose that this 47 migration defect might account at least in part for the fact that during in vivo infection significantly 48 lower numbers of ADAPko NK cells accumulate in the spleen i.e. the site of infection. In conclusion, 49 we show here that during systemic Lm infection in mice ADAP is essential for efficient cytokine and 50 chemokine production, cytotoxic capacity and migration of NK cells.
2020-05-27 | PXD016305 | Pride
Project description:Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. While most information on these cells comes from in vitro studies in humans or in vivo studies in mice, little is known about monocytes under human disease conditions. We investigated the role of monocytes during sepsis and its resolution in humans. A transcriptomal and functional analysis of blood monocytes from patients during gram negative sepsis and at recovery was performed. Monocytes from sepsis patients showed upregulation of a large number of pro-inflammatory genes and cytokines/chemokines, consistent with an ongoing systemic inflammation. However, these cells showed impairment to ex vivo endotoxin (LPS) challenge, displaying a quantitative decrease in the number of LPS-inducible genes. Moreover, they downregulated the expression of several pro-inflammatory cytokine/chemokine genes, activation marker genes and transcription factors associated with monocyte/macrophage activation, upon ex vivo LPS stimulation. Functionally, they downregulated expression of inflammatory cytokines/chemokines and antigen presentation-related molecules and functions. In contrast, genes and functions related to phagocytosis, anti-microbial activity and tissue remodeling where remained unaffected or even enhanced . Collectively, our observations suggest a genetic and functional re-programming of these cells during human sepsis progression. Understanding the molecular mechanisms which regulate this re-programming will allow to devise strategies which could modulate the response of these cells and hence, disease progression. Blood monocytes from gram-negative sepsis patients during sepsis (Sepsis) and following their recovery (Recovery/Basal) as well as healthy donor (control) were isolated. Thereafter, these cells were treated ex vivo with or without LPS for 3h and analysed for transcriptomic study.
2014-05-14 | E-GEOD-46955 | biostudies-arrayexpress
Project description:Our interest lies in how plants respond to bacterial pathogens. Over the past three years we have identified and documented reproducible, landmark biochemical and molecular events following the challenge of Arabidopsis with the phytopathogenic enterobacteria P. syringae. Significantly, our studies revealed 60% of cDNA-AFLP differentials not present on the 8,200 feature GeneChips and 20% absent from public EST databases (de Torres in press). We now seek to exploit this background using carefully defined time-points to analyse global changes in the Arabidopsis transcriptome using challenges selected to define gene targets implicated in (i) expression of basal immunity (ii) the establishment of successful parasitism (resistance) by a virulent pathogen (host). The results will provide a rationale for future functional assays of the identified pathways using transgenic knockouts and mutant analyses. Additionally, data will provide underpinning support for comparative proteomics of the defense response currently in progress with GARNet support using the same experimental parameters (BBSRC 32/P14635). We propose the following treatments: (i) Mock vs. DC3000hrpA @ 60 min: 60 minutes is subsequent to host immediate-early stress responses and will catalogue the innate responses induced by pathogen associated molecular patterns. The hrpA lesion will ensure no type III effectors influence transcriptional responses. Gene products induced at this time are predicted to potentiate latter host responses (2 treatments X 3 biological replicates = 6 chips). (ii) Mock vs. DC3000 vs. DC3000hrpA vs. DC3000::avrRpm1 @ 4 hours: A key time point previously defined where no macroscopic symptoms are visible but significant differences exist between compatible and incompatible interactions at the molecular and physiological levels. These treatments will serve to define the earliest genes induced by the complement of DC3000 type III effector and will specifically define genes/pathways suppressed by virulence factors in addition to those implicated in orchestration of the hypersensitive cell death. We will also include an incompatible interaction on a transgenic line expressing an RPM1 interacting protein, which fails to mount an HR but exhibits hyper-resistance. We predict this challenge will separate the resistance response (pathogen restriction) from that associated with hypersensitive cell death (5 treatments X 3 biological replicates = 15 chips). (iii) Mock vs. DC3000 vs. DC3000hrpA @ 14 hours: At 10 h before phenotypes are apparent in the DC3000 background, Type III effector delivery is well advanced and impact on host transcription maximal (3 treatments X 3 biological replicates = 9 chips). Keywords: time_series_design; pathogenicity_design; compound_treatment_design
2007-01-22 | GSE6176 | GEO