Diabetes mellitus has been a major public health problem worldwide, characterized by insulin resistance and dysfunction of β-cells. A previous study showed that Kindlin-2 loss in β-cells dramatically reduces insulin secretion and decreases β-cell mass, resulting in severe diabetes-like phenotypes. It suggests that Kindlin-2 in β-cells play an important role in regulating glucose homeostasis. However, the effect of Kindlin-2 on the function of β-cells under chronic hyperglycemia in diabetes has not been explored. Here we report that Kindlin-2 overexpression ameliorates diabetes and improves insulin secretion in mice induced by streptozocin. In contrast, Kindlin-2 insufficiency exacerbates diabetes and promotes β-cells dysfunction and inflammation in β-cells induced by a high-fat diet (HFD). In vitro, Kindlin-2 overexpression prevented high-glucose (HG)-induced dysfunction in β-cells. Kindlin-2 overexpression also decreased the expression of pro-inflammatory cytokines and NLRP3 inflammasome expression in β-cells exposed to HG. Furthermore, the loss of Kindlin-2 aggravates the expression of inflammatory cytokines and NLRP3 induced by HG in β-cells. Collectively, we demonstrate that Kindlin-2 protects against diabetes by inhibiting NLRP3 inflammasome activation.
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http://dx.doi.org/10.1016/j.bbrc.2022.04.131 | DOI Listing |
Immunol Rev
January 2025
Department of Internal Medicine and Paediatrics, Ghent University, Ghent, Belgium.
Inflammasomes are crucial mediators of both antimicrobial host defense and inflammatory pathology, requiring stringent regulation at multiple levels. This review explores the pivotal role of mitogen-activated protein kinase (MAPK) signaling in modulating inflammasome activation through various regulatory mechanisms. We detail recent advances in understanding MAPK-mediated regulation of NLRP3 inflammasome priming, licensing and activation, with emphasis on MAPK-induced activator protein-1 (AP-1) signaling in NLRP3 priming, ERK1 and JNK in NLRP3 licensing, and TAK1 in connecting death receptor signaling to NLRP3 inflammasome activation.
View Article and Find Full Text PDFJ Neurosci
January 2025
University of Miami Miller School of Medicine, Department of Biochemistry and Molecular Biology, Miami, FL 33136.
The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact post-stroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke.
View Article and Find Full Text PDFSci Immunol
January 2025
Department of Pathology and Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
The NLRP3 inflammasome plays a critical role in innate immunity and inflammatory diseases. NIMA-related kinase 7 (NEK7) is essential for inflammasome activation, and its interaction with NLRP3 is enhanced by K efflux. However, the mechanism by which K efflux promotes this interaction remains unknown.
View Article and Find Full Text PDFClin Rev Allergy Immunol
December 2024
Division of Allergy and Clinical Immunology, The Johns Hopkins Asthma & Allergy Center, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Room 3B.71, Baltimore, MD, 21224, USA.
Asthma is a chronic airway inflammatory disease that affects millions globally. Although glucocorticoids are a mainstay of asthma treatment, a subset of patients show resistance to these therapies, resulting in poor disease control and increased morbidity. The complex mechanisms underlying steroid-resistant asthma (SRA) involve Th1 and Th17 lymphocyte activity, neutrophil recruitment, and NLRP3 inflammasome activation.
View Article and Find Full Text PDFNeurochem Res
January 2025
Precision Pharmacy & Drug Development Center, Department of Pharmacy, Tangdu Hospital, Air Force Medical University, Xi'an, 710038, China.
Depression is a common and complex neuropsychiatric disorder affecting people of all ages worldwide, associated with high rates of relapse and disability. Neohesperidin (NEO) is a dietary flavonoid with applications in therapeutics; however, its effects on depressive-like behavior remain unknown. Here, we evaluated the effects of NEO on depressive-like behavior induced by chronic and unpredictable mild stress (CUMS).
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