scholarly journals A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

2020 ◽  
Author(s):  
Clyde A. Campbell ◽  
Oksana Fursova ◽  
Xiaoyi Cheng ◽  
Elizabeth Snella ◽  
Abbigail McCune ◽  
...  

AbstractGranulin (GRN) is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to utilize Granulin in the treatment of rheumatoid arthritis, frontotemporal dementia, and to enhance wound healing. How granulin contributes to each of these diverse biological functions, however, remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. Using a zebrafish model of granulin deficiency, we reveal that in the absence of granulin a (grna), myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages during normal and emergency myelopoiesis. In addition, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8 positively regulate grna expression. Importantly, we demonstrate functional conservation between the mammalian granulin and the zebrafish orthologue grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, opening a new field of study that has the potential to impact different aspects of the human health.

2021 ◽  
Vol 5 (3) ◽  
pp. 796-811
Author(s):  
Clyde A. Campbell ◽  
Oksana Fursova ◽  
Xiaoyi Cheng ◽  
Elizabeth Snella ◽  
Abbigail McCune ◽  
...  

Abstract Granulin is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to use granulin to treat rheumatoid arthritis and frontotemporal dementia and to enhance wound healing. But how granulin contributes to each of these diverse biological functions remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. We have taken advantage of the tissue-specific segregation of the zebrafish granulin paralogues to assess the functional role of granulin in hematopoiesis without perturbing other tissues. By using our zebrafish model of granulin deficiency, we revealed that during normal and emergency myelopoiesis, myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages in the absence of granulin a (grna), failing to express the myeloid-specific genes cebpa, rgs2, lyz, mpx, mpeg1, mfap4, and apoeb. Functionally, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8, positively regulates grna expression. In vivo imaging and RNA sequencing experiments show that grna inhibits the expression of gata1, leading to the repression of the erythroid program. Importantly, we demonstrated functional conservation between the mammalian granulin and the zebrafish ortholog grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, which opens a new field of study that can potentially have an impact on different aspects of human health and expand the therapeutic options for treating myeloid disorders such as neutropenia or myeloid leukemia.


2021 ◽  
Vol 12 (4) ◽  
pp. 488-492
Author(s):  
Guilherme Carneiro Montes

Zebrafish (Danio rerio) is a vertebrate animal used in animal model research with complex brains and behaviors similar to humans and associate with low coast become a model attractive for the academic community to seek zebrafish for scientific research. Studies on diseases of the central nervous system (CNS) have advanced and news therapeutic agents were developed for treatment these disorders. Reports suggest that the zebrafish model supports the neurodegenerative studies due functional conservation between human genes implicated in neurodegenerative disorders. The discovery of therapeutic compounds for CNS using the zebrafish model allows to show a neuroprotective action or neurotoxicity that might alter the behavioral changes. Neurotoxicity tests might perform in zebrafish’s embryos into 96 multi-well plates, which reduces the amount of substances used and cost. The bioactive compounds able to penetrate the blood-brain barrier (BBB) have important role physicochemical properties that might be desirable pharmacological effects and zebrafish trials allow if the substances might penetrate BBB and to exert central activity. The assays zebrafish are used to analyze nanoparticles that are small molecules used to explore variety applications in human health. Gold nanoparticles (AuNPs) has important properties which are extremely interest for pharmaceutical area such as drug delivery, cellular imaging, diagnostics, and therapeutic agents. Gold nanoparticles enhances Parkinson symptoms and improved neuroinflammation. Some studies show zebrafish might use to evaluate gold nanoparticles for human health hazard and toxicity studies. There is enormous potential for zebrafish in preclinical assays due to predict pharmacological and toxicity effects. Specific guidelines focused on methodologies in the zebrafish are needed to ensure adequate reproducible trials.


1988 ◽  
Vol 179 (1) ◽  
pp. 79-88 ◽  
Author(s):  
Robert P. Wersto ◽  
Fritz Herz ◽  
Robert E. Gallagher ◽  
Leopold G. Koss

1986 ◽  
Vol 261 (10) ◽  
pp. 4726-4731
Author(s):  
A Goldberger ◽  
L S Hnilica ◽  
S B Casey ◽  
R C Briggs

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 954.3-954
Author(s):  
S. Okita ◽  
H. Ishikawa ◽  
A. Abe ◽  
S. Ito ◽  
A. Murasawa ◽  
...  

Background:It has been suggested that perioperative use of biological disease-modifying anti-rheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients carries risks for the surgical-site infection and the delayed wound healing (DWH); however, the risk of DWH with perioperative use of bDMARDs has not reached a general consensus.Objectives:This retrospective study aimed to investigate the risk factors associated with DWH after orthopedic surgery in RA patients treated with bDMARDs.Methods:We reviewed medical records of 277 orthopedic procedures for 188 RA patients treated with bDMARDs between from 2014 to 2017 in Niigata Rheumatic Center. As preoperative nutritional status assessment, we evaluated body mass index (BMI), prognostic nutritional index (PNI), and CONtrolling NUTritional status (CONUT). In addition, we evaluated DAS28-CRP, DAS28-ESR, face scale for pain, global health (GH), and Health Assessment Questionnaire-Disability Index (HAQ-DI) to assess the disease activity. Univariate and multivariate logistic regression analyses were performed to evaluate the risk factor for DWH.Results:The major characteristics of the patients in 277 procedures were mean age of 63.2 years old and mean disease duration of 18.2 years. Surgical site were hand and wrist (145 procedures), foot and ankle (76), hip and knee (31), elbow and shoulder (24), and spine (1). Seventy-four patients were treated with tocilizumab, 62 with etanercept, 55 with golimumab, 49 with abatacept, 16 with infliximab, 15 with adalimumab, and 6 with certolizumab. According to nutritional assessment in PNI and CONUT, 63% (n=175) and 47% (n=130) were normal nourished patients, respectively.In 277 procedures, DWH were identified in 24 patients (8.6%). The following variables were significant in the univariate analyses: disease duration (OR 1.053; 95% CI 1.010–1.099; p=0.016), foot and ankle surgery (OR 7.091; 95% CI 2.130–23.603; p=0.001), tocilizumab (OR 0.286; 95% CI 0.093–0.881; p=0.029) (Table 1). These variables were entered into a multivariate model, and it was revealed that pre-operative use of tocilizumab (OR 0.265; 95% CI 0.074–0.953; p=0.042) and procedures in the foot and ankle (OR 6.915; 95% CI 1.914–24.976; p=0.003) were associated with an increased risk of DWH (Table 1).Conclusion:As previous study on tocilizumab described, the current retrospective study suggested that pre-operative use of tocilizumab and procedures in the foot and ankle were risk factors for DWH. Pre-operative disease activity and nutritional status were not independent risk factors for an increase in the prevalence of DWH.References:[1] Momohara S, Hashimoto J, Tsuboi H et al. Analysis of perioperative clinical features and complications after orthopaedic surgery in rheumatoid arthritis patients treated with tocilizumab in a real-world setting: Results from the multicentre tocilizumab in perioperative period (TOPP) study. Modern rheumatology. 2013, 23: 440-9.Disclosure of Interests:Shunji Okita: None declared, Hajime Ishikawa: None declared, Asami Abe: None declared, Satoshi Ito Speakers bureau: Abbvie,Eisai, Akira Murasawa: None declared, Keiichiro Nishida Grant/research support from: K. Nishida has received scholarship donation from CHUGAI PHARMACEUTICAL Co., Eisai Co., Mitsubishi Tanabe Pharma and AbbVie GK., Speakers bureau: K. Nishida has received speaking fees from CHUGAI PHARMACEUTICAL Co., Eli Lilly, Janssen Pharmaceutical K.K., Eisai Co. and AYUMI Pharmaceutical Corporation., Toshifumi Ozaki: None declared


2021 ◽  
Author(s):  
Junli Feng ◽  
Gongshuai Song ◽  
Yuanyuan Wu ◽  
Xi Chen ◽  
Jie Pang ◽  
...  

Plasmalogens (PLs) are critical to human health. Studies have reported a link between downregulation of PLs levels and cognitive impairments in patients with Alzheimer´s disease (AD). however, the underlying mechanisms...


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