The pro-apoptotic ARTS protein induces neutrophil apoptosis, efferocytosis, and macrophage reprogramming to promote resolution of inflammation
| Autor: | Prajakta Kalkar, Zohar Zvi Zamir, Sagie Schif-Zuck, Sarit Larisch, Amiram Ariel, Orly Zeytuni-Timor, Naama Maimon |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cancer Research Neutrophils Primary Cell Culture Clinical Biochemistry Nitric Oxide Synthase Type II Pharmaceutical Science Apoptosis Inflammation Peritonitis Inhibitor of Apoptosis Proteins Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Phagocytosis medicine Animals Humans Macrophage Efferocytosis Caspase Mice Knockout Pharmacology Arginase biology Biochemistry (medical) Zymosan Cell Biology Cellular Reprogramming XIAP Cell biology 030104 developmental biology Gene Expression Regulation Matrix Metalloproteinase 9 chemistry Cyclooxygenase 2 030220 oncology & carcinogenesis Macrophages Peritoneal biology.protein Cytokines Poly(ADP-ribose) Polymerases medicine.symptom Reprogramming Septins Signal Transduction |
| Zdroj: | Apoptosis. 25:558-573 |
| ISSN: | 1573-675X 1360-8185 |
| DOI: | 10.1007/s10495-020-01615-3 |
| Popis: | ARTS (Sept4_i2) is a pro-apoptotic protein and a product of the Sept4 gene. ARTS acts upstream of mitochondria to initiate caspase activation. ARTS induces apoptosis by specifically binding XIAP and allowing de-repression of active caspases required for Mitochondrial Outer Membrane Permeabilzation (MOMP). Moreover, ARTS promotes apoptosis by inducing ubiquitin-mediated degradation of both major anti-apoptotic proteins XIAP and Bcl-2. In the resolution phase of inflammation, the infiltrating leukocytes, which execute the acute innate response, undergo apoptosis and are subsequently cleared by phagocytic macrophages (i.e. efferocytosis). In this course, macrophages undergo reprogramming from inflammatory, to anti-inflammatory, and eventually to resolving macrophages that leave the injury sites. Since engulfment of apoptotic leukocytes is a key signaling step in macrophage reprogramming and resolution of inflammation, we hypothesized that a failed apoptosis in leukocytes in vivo would result in an impaired resolution process. To test this hypothesis, we utilized the Sept4/ARTS-/- mice, which exhibit resistance to apoptosis in many cell types. During zymosan A-induced peritonitis, Sept4/ARTS-/- mice exhibited impaired resolution of inflammation, characterized by reduced neutrophil apoptosis, macrophage efferocytosis and expression of pro-resolving mediators. This was associated with increased pro-inflammatory cytokines and reduced anti-inflammatory cytokines, secreted by resolution-phase macrophages. Moreover, ARTS overexpression in leukocytes in vitro promoted an anti-inflammatory behavior. Overall, our results suggest that ARTS is a key master-regulator necessary for neutrophil apoptosis, macrophage efferocytosis and reprogramming to the pro-resolving phenotype during the resolution of inflammation. |
| Databáze: | OpenAIRE |
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