Abstract
Neurodegeneration is a critical problem in aging populations and is characterized by severe central nervous system (CNS) inflammation. Macrophages closely regulate inflammation in the CNS and periphery by taking on different activation states. The source of inflammation in many neurodegenerative diseases has been preliminarily linked to a decrease in the CNS M2 macrophage population and a subsequent increase in M1-mediated neuroinflammation. The Recepteur D’Origine Nantais (Ron) is a receptor tyrosine kinase expressed on tissue-resident macrophages including microglia. Activation of Ron by its ligand, macrophage-stimulating protein, attenuates obesity-mediated inflammation in the periphery. An in vivo deletion of the ligand binding domain of Ron (Ron−/−) promotes inflammatory (M1) and limits a reparative (M2) macrophage activation. However, whether or not this response influences CNS inflammation has not been determined. In this study, we demonstrate that in homeostasis Ron−/− mice developed an inflammatory CNS niche with increased tissue expression of M1-associated markers when compared to age-matched wild-type (WT) mice. Baseline metabolic analysis of CNS tissue indicates exacerbated levels of metabolic stress in Ron−/− CNS. In a disease model of multiple sclerosis, experimental autoimmune encephalomyelitis, Ron−/− mice exhibit higher disease severity when compared to WT mice associated with increased CNS tissue inflammation. In a model of diet-induced obesity (DIO), Ron−/− mice exhibit exacerbated CNS inflammation with decreased expression of the M2 marker Arginase-1 (Arg-1) and a robust increase in M1 markers compared to WT mice following 27 weeks of DIO. Collectively, these results illustrate that activation of Ron in the CNS could be a potential therapeutic approach to treating various grades of CNS inflammation underlying neurodegeneration.
Highlights
Neuroinflammation is a critical underlying component of neurodegenerative diseases and exacerbates disease symptoms associated with Alzheimer’s (AD), Parkinson’s (PD), multiple sclerosis (MS), and with homeostatic aging [1, 2]
In order to determine the function of Recepteur D’Origine Nantais (Ron) in microglia, CHME-3 cells were pretreated with the Ron agonist Macrophage-stimulating protein (MSP), and the expression of Ron mRNA was assessed by qPCR (Figure 1A)
In order to determine whether Ron attenuates M1-mediated inflammation in microglia, CHME-3 cells were treated with LPS for 4 h in the presence or absence of MSP
Summary
Neuroinflammation is a critical underlying component of neurodegenerative diseases and exacerbates disease symptoms associated with Alzheimer’s (AD), Parkinson’s (PD), multiple sclerosis (MS), and with homeostatic aging [1, 2]. Neuroinflammation can be acute, such as in ischemic stroke, or chronic which supports long-term neuronal loss exhibited in progressive autoimmune diseases such as MS or neurogenerative states such as AD [3]. In degenerative diseases, these processes persist, leading to uncontrolled inflammation that becomes toxic to the CNS tissue proper, propels breakdown of the blood–brain barrier (BBB) and promotes subsequent tissue injury [4]. A longitudinal study of adults illustrated that individuals who exhibit higher BMI in their 30s and 40s have an earlier onset of dementia associated with Alzheimer’s [5]. In all cases of neuroinflammation, CNS macrophages such as tissue resident microglia are key innate immune cells that closely regulate the inflammatory process [6, 7]
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