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.”

“For example, the humanized anti-ST2 monoclonal antibody astegolimab effectively blocks ST2 signaling in TBI models, reversing IL-33/ YAP-mediated neuroprotective effects and thereby con - firming pathway specificity (Zhao et al. 2025).”

“While alterations in oligodendroglia have been reported in many neurodegenerative diseases (6–13, 23–28, 73, 74, 79, 80), including SCA1 (4, 5, 33), it remains largely unclear whether these changes actively drive disease progression or arise as secondary consequences.”

“…to an ischemic insult, spinal cord injury, or TBI several studies indicate that IL-33 expression directly following the injury is protective [56, 58–60] [61], and there perhaps would not be a need for soluble ST2 to ‘turn off’ IL-33 signalling unless it continued to more chronic timepoints as is…”

“This finding is in line with previous reports that in vivo administration of IL-33 increases the myelin content in the spinal cord following spinal cord trauma [24] and stroke [25].”

“At the same time, emerging evidence indicates that CNS-associated Tregs can acquire tissue-adapted reparative phenotypes involved in oligodendrogenesis, microglial modulation, and tissue remodeling through mediators such as amphiregulin, IL-10, TGF-β, and CCN3 [61, 75, 76].”

“31,32 Several of the proteins identi fi ed in the post-injury neuroin fl ammatory cascade have been linked to long-term outcome following sTBI, 20 but clinical intervention has yet to show therapeutic bene fi t. 15 Previously, we have reviewed existing literature and suggested candidate vascular…”