The Glia-Derived Alarmin IL-33 Orchestrates the Immune Response and Promotes Recovery following CNS Injury

“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses, respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”

“Costaining of IL-33 with the astrocyte marker ALDH1L1 (Cahoy et al., 2008) demonstrated that these cells were astrocytes, which express IL-33 in gray matter regions (i.e., neocortex) but not in white matter (i.e., corpus callosum ; Figures 1F and 1G).”

“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses , respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”

“Error bars represent mean ± SEM; *p % 0.05; **p % 0.01; ***p % 0.001. relative to WT counterparts after SCI, as assessed by Basso mouse scale (Basso et al., 2006 ) (Figure 3E).”

“Interleukin (IL)-33 is a nuclear alarmin of the IL-1 cytokine family released by cell damage and is well characterized as an immune activator in conditions such as asthma (Liew et al., 2010), allergy (Oboki et al., 2010), and sepsis (Alves-Filho et al., 2010).”

“Neurons and glia directly damaged by the initial insult die, both necrotically and apoptotically (Grossman et al., 2001; Liu et al., 1997; Lytle and Wrathall, 2007), followed by secondary degeneration—a spread of damage through apoptotic death of initially uninjured neurons (Dusart and Schwab,…”

“A potential explanation of these dual aspects is macrophage phenotype, with the alternative (M2) and classical (M1) polarization correlating with beneficial or detrimental responses, respectively (Kigerl et al., 2009; Kroner et al., 2014; Schmitz et al., 2005; Shechter et al., 2009, 2013).”

“Given previous reports showing that IL-33 can polarize toward an ‘‘M2’’ (IL-4-activated) macrophage skew (Kurowska-Stolarska et al., 2009) and that M2 macrophages promote neuronal survival (Kigerl et al.”

“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”

“Upon release from necrotically dying cells (Lüthi et al., 2009), IL-33 binds IL-33R, a heterodimer of IL-1RAcP and ST2, and initiates an intracellular cascade involving MyD88 and NFkB (Liew et al.”

“Interleukin (IL)-33 is a nuclear alarmin of the IL-1 cytokine family released by cell damage and is well characterized as an immune activator in conditions such as asthma (Liew et al., 2010), allergy (Oboki et al., 2010), and sepsis (Alves-Filho et al., 2010).”

“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”

“…and glia directly damaged by the initial insult die, both necrotically and apoptotically (Grossman et al., 2001; Liu et al., 1997; Lytle and Wrathall, 2007), followed by secondary degeneration—a spread of damage through apoptotic death of initially uninjured neurons (Dusart and Schwab, 1994).”

“, 2010), and sepsis (Alves-Filho et al., 2010).”

“Other studies have alluded to the importance of IL-33 in other CNS pathologies: IL-33 treatment mitigates pathology of EAE (Jiang et al., 2012) and human Alzheimer’s”

“Neurons and glia directly damaged by the initial insult die, both necrotically and apoptotically (Grossman et al., 2001; Liu et al., 1997; Lytle and Wrathall, 2007), followed by secondary degeneration—a spread of damage through apoptotic death of initially uninjured neurons (Dusart and Schwab,…”

“To address the role of IL-33 in recovery from CNS trauma, we subjected IL-33 –/– and wild-type (WT) mice to an optic nerve crush injury (Yoles and Schwartz, 1998), a model that is dependent on immune assistance for optimal neuronal survival (Kipnis et al., 2004; Walsh et al., 2015).”

“Astrocytes have been suggested as the cellular source of IL-33 (Yasuoka et al., 2011), but this remains poorly characterized in vivo.”

“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”

“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”

“The immune system detects and rapidly responds to injury with a cascade of peripheral effectors and soluble molecules (Trivedi et al., 2006).”

“Error bars represent mean ± SEM; *p% 0.05; **p% 0.01; ***p% 0.001). disease is correlated with decreased CNS IL-33 expression (Chapuis et al., 2009).”

“It has previously been reported that the majority of Arg1 + cells entering the CNS injury site are infiltrating monocytes (Hsieh et al., 2013), and we confirmed by immunofluorescent analysis of the 1DPI injury site that there are fewer Arg1 + cells in IL-33 –/– animals relative to WT (Figures 4F…”

“To address the role of IL-33 in recovery from CNS trauma, we subjected IL-33 and wild-type (WT) mice to an optic nerve crush injury (Yoles and Schwartz, 1998), a model that is dependent on immune assistance for optimal neuronal survival (Kipnis et al., 2004; Walsh et al., 2015).”

“Neurons and glia directly damaged by the initial insult die, both necrotically and apoptotically (Grossman et al., 2001; Liu et al., 1997; Lytle and Wrathall, 2007), followed by secondary degeneration—a spread of damage through apoptotic death of initially uninjured neurons (Dusart and Schwab,…”

“RGCs are distributed unevenly across themouse retina, becoming less dense further away from the optic disk (Ortı́n-Martı́nez et al., 2014).”

“To reaffirm the critical role of monocyte recruitment in contributing to impairment in IL-33 –/– mice, we sought to enhance recruitment by delivering CCL2, a major chemokine for recruitment of peripheral monocytes into tissues including the CNS (Ma et al., 2002).”

“Previous studies have shown that cultured glia produce the chemokine CCL2 (MCP1) in response to IL-33 stimulation (Kempuraj et al., 2013).”

“To assess whether IL-33-expressing cells must be actually damaged for IL-33 to have an effect, we used a second retinal injury model, intraocular glutamate injection (Schori et al., 2002).”

“The overall impact of this immune response remains debated, as it has potential to drive both beneficial (Shechter et al., 2013; Walsh et al., 2015; Walsh et al., 2014) and detrimental (Evans et al., 2014; Kroner et al., 2014) effects on recovery.”

“Soon thereafter, they adopt an amoeboid shape (415) before migrating to the lesion area in response to alarmins such as IL-33, IL-1B, and TNF- released as soon as 15 min after the lesion (127, 323).”