Glia Maturation Factor Induces Interleukin-33 Release from Astrocytes: Implications for Neurodegenerative Diseases

Abstract

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD) and Multiple sclerosis (MS) involve activation of glial cells and release of inflammatory mediators leading to death of neurons. Glia maturation factor (GMF) is up-regulated in the central nervous system (CNS) in these neurodegenerative diseases. Interleukin-33 (IL-33) is highly expressed constitutively in the CNS. We have treated mouse astrocytes, mixed culture with glial cells and neurons, and only neurons with GMF and/or IL-33 in vitro. Both GMF and IL-33-induced chemokine (C-C motif) ligand 2 (CCL2) release in a dose and time-dependent manner. We report that GMF induced IL-33 release, and that IL-33 augments GMF-induced TNF-α release from mouse astrocytes. IL-33 induces CCL2, TNF-α and nitric oxide release through phosphorylation of ERK in mouse astrocytes. Incubation of mixed culture containing glial cells and neurons or only neuronal culture with IL-33 reduced the number of neurons positive for microtubule-associated protein 2. In conclusion, IL-33 augments GMF-mediated neuroinflammation and may provide a new drug target for neurodegenerative and autoimmune diseases.

Targeting IL-33 in Autoimmunity and Inflammation

“…Release of IL-33 from astrocytes was induced by glial maturation factor, implicating them in neurodegenerative diseases (Kempuraj et al, 2013). Moreover, incubation of mouse astrocytes with amyloid-b1-42 increased IL-33 expression (Xiong et al, 2014).…”

“…IL-33 is a new member of the IL-1 family that regulates innate and adaptive immune systems to promote inflammatory responses (Dinarello, 2009). IL-33 is mainly expressed by keratinocytes, epithelial and endothelial cells (Moussion et al, 2008), as well as by human monocytes (Nile et al, 2010) and mouse astrocytes (Kempuraj et al, 2013). IL-33 acts as an alarmin against injury-induced stress, pathogens, or cell death by activating local immune cells (Lukens et al, 2012;Lunderius-Andersson et al, 2012).…”

Cross-Talk between Glia, Neurons and Mast Cells in Neuroinflammation Associated with Parkinson’s Disease

“…Resident brain mast cells are present adjacent to blood vessels, glial cells and nerves in the central nervous system (CNS), and communicate with these cells in pathophysiological conditions (Chikahisa et al, 2013). Activated mast cells release several multifunctional proinflammatory mediators including interleukin-1beta (IL-1β), IL-6, IL-8, IL-17, IL-18, IL-33, tumor necrosis factor-alpha (TNF-α), granulocyte macrophage-colony stimulating factor (GM-CSF), chemokine (C-C motif) ligand 2 (CCL2), CCL5, matrix metalloproteinase-3 (MMP-3), substance P, histamine, tryptase, prostaglandins, reactive oxygen species (ROS), reactive nitrogen species (RNS) and nitric oxide (NO) during an inflammatory response (Mekori and Metcalfe, 2000; Kalesnikoff and Galli, 2008; Sismanopoulos et al, 2012; Theoharides et al, 2012; Kempuraj et al, 2013). Persistent microglial activation and chronic neuroinflammation are implicated in the PD pathogenesis (Grimmig et al, 2016; Li et al, 2016).…”

Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

“…Our results will be briefly described here, and at length in Sections 3.1 and 3.2. As described previously, IL-33 can stimulate CCL2 production by mixed glia in vitro (Gadani et al, 2015b;Kempuraj et al, 2013), and IL-33 -/-mice show significantly reduced production of several chemokines at the injury site after SCI (Gadani et al, 2015b). This defect in chemokine expression was coupled with reduced recruitment of peripheral monocytes, impaired recovery, and increased lesion volume after SCI, and with decreased neuronal survival after optic nerve crush (Gadani et al, 2015b).…”

“…Seven days after glutamate injection, we counted RGCs by labeling them using their specific transcription factor Brn3a Optic nerve injury is a model of severe CNS damage. The majority of RGCs die in WT mice, making it challenging to sensitively detect further impairment due to a floor IL-33 stimulation (Kempuraj et al, 2013). We sought to explore other chemokines that could be induced with IL-33 stimulation by performing a luminex chemokine assay on supernatants of IL-33 treated mixed glial cultures.…”