Optineurin inhibition impedes type II collagen challenged dendritic cell migration
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1004646 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25618975_1.fastq.gz | Fastqsanger.gz | |||
| SRR25618975_2.fastq.gz | Fastqsanger.gz | |||
| SRR25618976_1.fastq.gz | Fastqsanger.gz | |||
| SRR25618976_2.fastq.gz | Fastqsanger.gz | |||
| SRR25618977_1.fastq.gz | Fastqsanger.gz |
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Project description:Due to the maturation, migration and antigen presentation functions, dendritic cells (DCs) play a central role in the development of many autoimmune diseases, like rheumatoid arthritis, multiple sclerosis and dermatitis. However, the molecular regulatory process of disease- or antigen-specific DC activation remains elusive. We show that deletion of Optineurin (OPTN) effectively impairs type II collagen (CII), the main autoantigen for rheumatoid arthritis, challenged DC migration, thus ameliorating collagen-induced arthritis. Transcriptome analyses indicate that OPTN promotes the expressions of migration related genes. Our findings thus indicate that OPTN is an important regulator of CII-pulsed DC migration, which may be of potential value for the accurate treatment of rheumatoid arthritis.
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Project description:This study aimed to identify genes that are linked with optineurin expression using a combined siRNA-microarray approach Keywords: siRNA treatment study
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Project description:Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) linking innate and adaptive immune response. DCs are crucial for initiating adaptive immune responses for elimination of invading pathogens and also in inducing immune tolerance toward harmless components to maintain immune homeostasis. Results provide insight into the function of optineurin and its role in the maturation and function of DCs.
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Project description:Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention.
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Project description:Systemic sclerosis (SSc) is a devastating disease affecting the skin and internal organs. Dermal fibrosis manifests early and Modified Rodnan Skin Scores (MRSS) correlate with disease progression. Transcriptomics of SSc skin biopsies suggest the role of the in vivo microenvironment in maintaining the pathological myofibroblasts. Therefore, defining the structural changes in dermal collagen in SSc patients could inform our understanding of fibrosis pathogenesis. Here, we report a method for quantitative whole-slide image analysis of dermal collagen from SSc patients, and our findings of more aligned dermal collagen bundles in diffuse cutaneous SSc (dcSSc) patients. Using the bleomycin-induced mouse model of SSc, we identified a distinct high dermal collagen bundle alignment gene signature, characterized by a concerted upregulation in cell migration, adhesion, and guidance pathways, and downregulation of spindle, replication, and cytokinesis pathways. Furthermore, increased bundle alignment induced a cell migration gene signature in fibroblasts in vitro, and these cells demonstrated increased directed migration on aligned ECM fibers that is dependent on expression of Arhgdib (Rho GDP-dissociation inhibitor 2). Our results indicate that increased cell migration is a cellular response to the increased collagen bundle alignment featured in fibrotic skin. Moreover, many of the cell migration genes identified in our study are shared with human SSc skin and may be new targets for therapeutic intervention.
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Project description:Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet, how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) is essential for healthy vision. Disrupted autophagy due to mTOR overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting LC3, which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, TRPML1 (transient receptor potential-mucolipin 1)-dependent manner. RNAseq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment, and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard metabolic fitness of the RPE through the organismal lifespan.
2023-08-15 | GSE237291 | GEO
Project description:Balancing the competing demands of phagolysosomal degradation and autophagy is a significant challenge for phagocytic tissues. Yet, how this plasticity is accomplished in health and disease is poorly understood. In the retina, circadian phagocytosis and degradation of photoreceptor outer segments by the postmitotic retinal pigment epithelium (RPE) is essential for healthy vision. Disrupted autophagy due to mTOR overactivation in the RPE is associated with blinding macular degenerations; however, outer segment degradation is unaffected in these diseases, indicating that distinct mechanisms regulate these clearance mechanisms. Here, using advanced imaging and mouse models, we identify optineurin as a key regulator that tunes phagocytosis and lysosomal capacity to meet circadian demands and helps prioritize outer segment clearance by the RPE in macular degenerations. High-resolution live-cell imaging implicates optineurin in scissioning outer segment tips prior to engulfment, analogous to microglial trogocytosis of neuronal processes. Optineurin is essential for recruiting LC3, which anchors outer segment phagosomes to microtubules and facilitates phagosome maturation and fusion with lysosomes. This dynamically activates transcription factor EB (TFEB) to induce lysosome biogenesis in an mTOR-independent, TRPML1 (transient receptor potential-mucolipin 1)-dependent manner. RNAseq analyses show that expression of TFEB target genes temporally tracks with optineurin recruitment, and that lysosomal and autophagy genes are controlled by distinct transcriptional programs in the RPE. The unconventional plasma membrane-to-nucleus signaling mediated by optineurin ensures outer segment degradation under conditions of impaired autophagy in macular degeneration models. Independent regulation of these critical clearance mechanisms would help safeguard metabolic fitness of the RPE through the organismal lifespan.
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