Metallothionein 3-Zinc Axis Suppresses Caspase-11 Inflammasome Activation and Impairs Antibacterial Immunity
| Autor: | Debabrata Chowdhury, Jason C. Gardner, Abhijit Satpati, Suba Nookala, Santhosh Mukundan, Aleksey Porollo, Julio A. Landero Figueroa, Kavitha Subramanian Vignesh |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Lipopolysaccharide
Inflammasomes Immunology non-canonical inflammasome Inflammation Caspase-11 macrophage Mice chemistry.chemical_compound medicine Animals Humans Immunology and Allergy Metallothionein caspase-11 non-canonical inflammasome innate immunity Caspase Original Research Innate immune system biology Effector Macrophages zinc MT3 Interleukin Inflammasome RC581-607 metallothionein Metallothionein 3 Cell biology Mice Inbred C57BL chemistry Caspases biology.protein medicine.symptom Immunologic diseases. Allergy Gram-Negative Bacterial Infections Intracellular medicine.drug |
| Zdroj: | Frontiers in Immunology, Vol 12 (2021) Frontiers in Immunology |
| ISSN: | 1664-3224 |
| Popis: | Non-canonical inflammasome activation by mouse caspase-11 (or human CASPASE- 4/5) is crucial for the clearance of certain gram-negative bacterial infections, but can lead to severe inflammatory damage. Factors that promote non-canonical inflammasome activation are well recognized, but less is known about the mechanisms underlying its negative regulation. Herein, we identify that the caspase-11 inflammasome in mouse and human macrophages (Mϕ) is negatively controlled by the zinc (Zn2+) regulating protein, metallothionein 3 (MT3). Upon challenge with intracellular lipopolysaccharide (iLPS), Mϕ increased MT3 expression that curtailed the activation of caspase-11 and its downstream targets caspase-1 and interleukin (IL)-1β. Mechanistically, MT3 increased intramacrophage Zn2+ to downmodulate the TRIF-IRF3-STAT1 axis that is prerequisite for caspase-11 effector function. MT3 suppressed activation of the caspase-11 inflammasome, while caspase-11 and MT3 synergized in impairing antibacterial immunity. The present study identifies an important yin-yang relationship between the non-canonical inflammasome and MT3 in controlling inflammation and immunity to gram- negative bacteria.GRAPHICAL ABSTRACT |
| Databáze: | OpenAIRE |
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