Inflammation has been reported to be intimately linked to the development or worsening of several non-infectious diseases. A number of chronic conditions such as cancer, diabetes, cardiovascular disorders, autoimmune diseases, and neurodegenerative disorders emerge as a result of tissue injury and genomic changes induced by constant low-grade inflammation in and around the affected tissue or organ. The existing therapies for most of these chronic conditions sometimes leave more debilitating effects than the disease itself, warranting the advent of safer, less toxic, and more cost-effective therapeutic alternatives for the patients. For centuries, flavonoids and their preparations have been used to treat various human illnesses, and their continual use has persevered throughout the ages. This review focuses on the anti-inflammatory actions of flavonoids against chronic illnesses such as cancer, diabetes, cardiovascular diseases, and neuroinflammation with a special focus on apigenin, a relatively less toxic and non-mutagenic flavonoid with remarkable pharmacodynamics. Additionally, inflammation in the central nervous system (CNS) due to diseases such as multiple sclerosis (MS) gives ready access to circulating lymphocytes, monocytes/macrophages, and dendritic cells (DCs), causing edema, further inflammation, and demyelination. As the dearth of safe anti-inflammatory therapies is dire in the case of CNS-related disorders, we reviewed the neuroprotective actions of apigenin and other flavonoids. Existing epidemiological and pre-clinical studies present considerable evidence in favor of developing apigenin as a natural alternative therapy against chronic inflammatory conditions.
Dendritic cells (DCs) within the CNS are recognized to play an important role in the effector phase and propagation of the immune response in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis. However, the mechanisms regulating DC trafficking into the CNS still need to be characterized. In this study, we show by performing intravital fluorescence videomicroscopy of the inflamed spinal cord white-matter microvasculature in SJL mice with EAE that immature, and to a lesser extent, LPS-matured, bone marrow-derived DCs efficiently interact with the CNS endothelium by rolling, capturing, and firm adhesion. Immature but not LPS-matured DCs efficiently migrated across the wall of inflamed parenchymal microvessels into the CNS. Blocking α4 integrins interfered with the adhesion but not the rolling or capturing of immature and LPS-matured DCs to the CNS microvascular endothelium, inhibiting their migration across the vascular wall. Functional absence of β1 integrins but not of β7 integrins or α4β7 integrin similarly reduced the adhesion of immature DCs to the CNS microvascular endothelium, demonstrating that α4β1 but not α4β7 integrin mediates this step of immature DCs interaction with the inflamed blood-brain barrier during EAE. Our study shows that during EAE, especially immature DCs migrate into the CNS, where they may be crucial for the perpetuation of the CNS-targeted autoimmune response. Thus therapeutic targeting of α4 integrins affects DC trafficking into the CNS and may therefore lead to the resolution of the CNS autoimmune inflammation by reducing the number of CNS professional APCs.
Apigenin, a natural flavonoid, found in several plants, fruits, vegetables, herbs, and spices, is known to have anti-oxidant and anti-inflammatory properties that are evident in the use of these substances for centuries as medicinal approaches to treat asthma, insomnia, Parkinson's disease, neuralgia, and shingles. However, there is a considerable dearth of information regarding its effect on immune cells, especially dendritic cells (DC) that maintain the critical balance between an immunogenic and tolerogenic immune response, in an immunospecialized location like the central nervous system (CNS). In this paper we looked at the anti-inflammatory properties of Apigenin in restoration of immune function and the resultant decrease in neuroinflammation. In vivo, a significant reduction in severity of experimental autoimmune encephalomyelitis (EAE) progression and relapse was observed in C57BL/6 (progressive) and SJL/J (relapse-remitting) mouse models of multiple sclerosis upon treatment with Apigenin. Apigenin treated EAE mice show decreased expression of α4 integrin and CLEC12A on splenic DCs and an increased retention of immune cells in the periphery compared to untreated EAE mice. This correlated consequently with immunohistochemistry findings of decreased immune cell infiltration and reduced demyelination in the CNS. These results indicate a protective role of Apigenin against the neurodegenerative effects resulting from the entry of DC stimulated pathogenic T cells into the CNS thus implicating a potential therapy for neuroinflammatory disease.
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