Gene expression of mouse brain and mouse microglia in NRROS WT and NRROS KO animals
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE96938 | GEO | 2017/04/07
REPOSITORIES: GEO
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Project description:Mice deficient in NRROS exhibit neurological phenotype similar to ALS. Our previous work showed that in phagocytes, NRROS regulates the degradation of Nox2, the enzymatic component of the NADPH oxidase that generates reactive oxygen species. NRROS is expressed in phagocytes, including macrophages, neutrophils and microglia but not neurons. Previous results on RNA-sequencing from WT and NRRO KO CD11b+ population (NGS601) identified perivascular macrophage (pvm)-like expression profile in NRROS KO cells. FACS data revealed a loss of microglia and concomitant gain of pvm-like cells in the brains of NRROS KO mice.
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Project description:Mycobacterium tuberculosis’success as a pathogen comes from itsability to evade degradation by macrophages. Normally macro-phages clear microorganisms that activate pathogen-recognitionreceptors (PRRs) through a lysosomal-trafficking pathway called“LC3-associated phagocytosis”(LAP). AlthoughM.tuberculosisac-tivates numerous PRRs, for reasons that are poorly understoodLAP does not substantially contribute toM.tuberculosiscontrol.LAP depends upon reactive oxygen species (ROS) generated byNADPH oxidase, butM.tuberculosisfails to generate a robustoxidative response. Here, we show that CpsA, a LytR-CpsA-Psr(LCP) domain-containing protein, is required forM.tuberculosisto evade killing by NADPH oxidase and LAP. Unlike phagosomescontaining wild-type bacilli, phagosomes containing theΔcpsAmutant recruited NADPH oxidase, produced ROS, associated withLC3, and matured into antibacterial lysosomes. Moreover, CpsAwas sufficient to impair NADPH oxidase recruitment to fungal par-ticles that are normally cleared by LAP. Intracellular survival of theΔcpsAmutant was largely restored in macrophages missing LAPcomponents (Nox2,Rubicon,Beclin,Atg5,Atg7,orAtg16L1) butnot in macrophages defective in a related, canonical autophagypathway (Atg14,Ulk1,orcGAS). TheΔcpsAmutant was highlyimpaired in vivo, and its growth was partially restored in micedeficient in NADPH oxidase,Atg5,orAtg7, demonstrating thatCpsA makes a significant contribution to the resistance ofM.tu-berculosisto NADPH oxidase and LC3 trafficking in vivo. Overall,our findings reveal an essential role of CpsA in innate immuneevasion and suggest that LCP proteins have functions beyond theirpreviously known role in cell-wall metabolism.
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Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AM) are the predominant immune cell in the airways at steady state, and limiting their activation is important given constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well-understood. Here, we show a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, as studied using CGD mice or mice with selective loss of NOX2 primarily in macrophages. AM lacking NOX2 have increased cytokine responses to TLR2 and TLR4 stimulation ex vivo. Moreover, between 4 and 12 weeks of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AM with epigenetic and transcriptional profiles reflecting immune activation compared to WT AM. The presence of CD11bhigh AM in CGD mice correlated with increased numbers of alveolar neutrophils and proinflammatory cytokines at steady state as well as increased lung inflammation following insults. Moreover, deletion of NOX2 primarily in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying pro-inflammatory sequela. Additionally, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue-specific as these changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that absence of NOX2 in alveolar macrophages leads to their pro-inflammatory remodeling and dysregulates alveolar homeostasis.
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Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation. Genetic defects in NOX2 result in chronic granulomatous disease (CGD), associated with microbial infections and inflammatory disorders, often involving the lung. Alveolar macrophages (AM) are the predominant immune cell in the airways at steady state, and limiting their activation is important given constant exposure to inhaled materials, yet the importance of NOX2 in this process is not well-understood. Here, we show a previously undescribed role for NOX2 in maintaining lung homeostasis by suppressing AM activation, as studied using CGD mice or mice with selective loss of NOX2 primarily in macrophages. AM lacking NOX2 have increased cytokine responses to TLR2 and TLR4 stimulation ex vivo. Moreover, between 4 and 12 weeks of age, mice with global NOX2 deletion developed an activated CD11bhigh subset of AM with epigenetic and transcriptional profiles reflecting immune activation compared to WT AM. The presence of CD11bhigh AM in CGD mice correlated with increased numbers of alveolar neutrophils and proinflammatory cytokines at steady state as well as increased lung inflammation following insults. Moreover, deletion of NOX2 primarily in macrophages was sufficient for mice to develop an activated CD11bhigh AM subset and accompanying pro-inflammatory sequela. Additionally, we showed that the altered resident macrophage transcriptional profile in the absence of NOX2 is tissue-specific as these changes were not seen in resident peritoneal macrophages. Thus, these data demonstrate that absence of NOX2 in alveolar macrophages leads to their pro-inflammatory remodeling and dysregulates alveolar homeostasis.
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Project description:The leukocyte NADPH oxidase 2 (NOX2) plays a key role in pathogen killing and immunoregulation
| PRJNA816856 | ENA