Investigation of Novel Immuno-Metabolic Mechanisms Regulating Inflammasome and Macrophage Activation

Abstract

Inflammation is the immune system's response to injurious stimuli, such as pathogens, toxic compounds, damaged cells, irradiation, and acts by eliminating harmful stimuli and initiating the healing process. Acute inflammation is an essential as well as a tightly balanced homeostatic process that preceded by the migration of leukocytes from the vasculature into the injury site to eradicate the infection. Further, the pro‐resolving response of the immune system promotes tissue repair. However, if the inflammation is unregulated or becomes prolonged by simultaneous destruction and repair of tissue, it leads to chronic inflammation. It involves a progressive change in immune cells type, present at the site of damage/injury. Chronic inflammation is the root cause of many chronic diseases, including metabolic (obesity, insulin resistance), neurodegenerative (Alzheimer), autoimmune and auto-inflammatory diseases (Rheumatoid arthritis and Lupus or Cryopyrin associated periodic syndrome).[1] Monocytes, as well as macrophages, are the 'big devourer' of the immune system. Macrophages reside in every tissue in the form of microglia, Kupffer cells and osteoclasts, alveolar cells, histocytes, and Langerhans cells where they engulf pathogens, apoptotic cells and produce immune effector molecules.[1] In the event of infection or tissue damage, monocytes quickly access the site and differentiate into tissue macrophages. These cells have a central role in protecting the host by eliminating pathogens and instruct other immune cells. However, they also cause the pathogenesis of degenerative and inflammatory disorders.[1] Following injury or infection, macrophages usually elicit an inflammatory response by producing proinflammatory mediators such as TNFα (tumor necrosis factor α), IL-1β (Interleukin- 1β) and nitric oxide (ΝΟ). These mediators participate to trigger many anti-microbial mechanisms, including oxidative pathways that contribute to the killing of invading microbes.[1,2] In macrophages, the production of mature IL-1β involves several steps. Firstly there is the transcription of IL-1β mRNA often termed as pro-IL-1β. This is followed by the conversion of pro-IL-1β into mature IL-1β, which is subsequently secreted. Formation of mature IL-1β involves caspase-1 and inflammasome activation.[3] The inflammasome is a cytosolic multi-protein complex, consists of NLRP3, ASC, Procaspase-1. Toll-like Receptors (TLRs) which detect pathogenic micro-organism and sterile stressors have been shown to participate in inflammasome activation.[3] TLRs stimulation induces NFκB dependent transcription of genes that encodes inflammasome components including NLRP3, ProIL-1β, and ProIL18 and downstream effector molecules. It is a critical step in priming before inflammasome complex formation by ATP.[3] Variety of PAMPs (Pattern associated molecular pattern)/DAMPs (Danger associated molecular pattern) such as fatty acids, ceramides, protein aggregates (islet amyloid polypeptide; β-amyloid), crystals (sodium urate, cholesterol, asbestos, calcium pyrophosphate, silica, alum), pore-forming bacterial toxins such as nigericin, hemozoin as well as extracellular ATP, hyaluronic acid promotes NLRP3 complex formation to convert procaspase-1 into active caspase-1 which in-turn process proIL-1β into an active form of IL-1β.[4] IL-1β activates many responses including the immediate recruitment of neutrophils to the sites of inflammation or infection, stimulation of the endothelial adhesion molecules, chemokines as well as cytokines, induction of the febrile response, and specific type of adaptive immunity like the Th17 response, therefore, exhibits its protective action against infections.[5]