Enhanced susceptibility of ADAP-deficient mice to Listeria monocytogenes infection is associated with an altered phagocyte phenotype and function
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PROVIDER: PRJNA734518 | ENA |
REPOSITORIES: ENA
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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: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 monocytes. Despite high phagocyte numbers in the 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 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.
| S-EPMC8515145 | biostudies-literature
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: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: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: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:During mononuclear phagocyte system evolution, monocytes differentiate into pro-tumorigenic TAMs. We used single cell RNA sequencing (scRNA-seq) to analyze the characteristics of mononuclear phagocyte in colorectal cancer
2023-07-01 | GSE217774 | GEO
Project description:Murine mononuclear phagocyte lineage cells
| PRJNA630056 | ENA
Project description:The mechanisms that govern organelle remodeling remain poorly defined. Lysosomes degrade cargo from various routes including endocytosis, phagocytosis and autophagy. For phagocytes, lysosomes are a kingpin organelle since they are essential to kill pathogens and process and present antigens. During phagocyte activation, lysosomes undergo a striking reorganization, changing from dozens of globular structures to a tubular network, in a process that requires the phosphatidylinositol-3-kinase-AKT-mTOR signalling pathway. Here, we show that lysosomes undergo a remarkable expansion in volume and holding capacity during phagocyte activation within 2 h of LPS stimulation. Lysosome expansion was paralleled by an increase in lysosomal protein levels, but this was unexpectedly independent of TFEB and TFE3 transcription factors, known to scale up lysosome biogenesis. Instead, we demonstrate a hitherto unappreciated mechanism of acute organelle expansion via mTORC1-dependent increase in translation of mRNAs encoding key lysosomal proteins. Importantly, mTORC1-dependent increase in translation activity was necessary for efficient and rapid antigen presentation by dendritic cells. Collectively, we identified a previously unknown and functionally relevant mechanism for lysosome expansion that relies on mTORC1-dependent enhanced translation of mRNAs to boost protein synthesis and lysosome biogenesis in response to an infection signal.
2020-01-07 | GSE136470 | GEO