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

Abstract

Inflammation is a prominent feature of CNS injury that heavily influences neuronal survival, yet the signals that initiate and control it remain poorly understood. Here we identify the nuclear alarmin, interleukin (IL)-33, as an important regulator of the innate immune response after CNS injury. IL-33 is expressed widely throughout the healthy brain and is concentrated in white mater due to predominant expression in post-mitotic oligodendrocytes. IL-33 is released immediately after CNS injury from damaged oligodendrocytes, acting on local astrocytes and microglia to induce chemokines critical for monocyte recruitment. Mice lacking IL-33 have impaired recovery after CNS injury, which is associated with reduced myeloid cell infiltrates and decreased induction of M2 genes at the injury site. These results demonstrate a novel molecular mediator contributing to immune cell recruitment to the injured CNS and may lead to new therapeutic insights in CNS injury and neurodegenerative diseases.

Interleukin 33 Initiates CNS Inflammation Following Traumatic Injury

“…mouse), we demonstrated that IL-33 is abundantly expressed in the healthy brain, being expressed by myelinating oligodendrocytes and gray matter astrocytes (See results) (Gadani et al, 2015b). This observation has since been repeated by other groups.…”

“…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).…”

“…Further studies have confirmed that IL-33 is a critical inducer of chemokines in various CNS injury models (Gadani et al, 2015b;Xi et al, 2016), and it is likely affecting both astrocytes and microglia (Gadani et al, 2015b). By RT-PCR ST2 mRNA is highest on microglia at baseline, but interestingly is downregulated by microglia and upregulated by astrocytes after injury (Gadani et al, 2015b).…”

Positive selection of IL‐33 in adaptive immunity of domestic Chinese goats

“…(2016) worked on gene IL‐32‐positive selection and different phylogenetic analyses in different animals. Interleukin (IL)‐32 is documented as pro‐inflammatory cytokine that plays substantial role in various biological processes, whereas the role of IL‐33 has been predictable in various diseases, such as cardiovascular diseases (Miller & Liew, 2011), especially allergic asthma (Liew, 2012; Saluja et al., 2015), allergies, chronic inflammation of the gut (Lopetuso et al., 2013), disorders of the central nervous system (Gadani et al., 2015), and rheumatoid arthritis (Palmer & Gabay, 2011). The function of IL‐33 is different from IL‐32; however, the positive selection of IL‐32 supports the current study of IL‐33.…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…IL-33, a cytokine belonging to the IL-1 family, is constitutively expressed in oligodendrocytes and astrocytes, as well as endothelial cells [185]. IL-33 undergoes activating cleavage by caspase-1 and interacts with a host of immune cells to shift the neuroinlammatory response towards neuroprotective, anti-inlammatory microglial and Th2 cell phenotypes, increasing the release of anti-inlammatory cytokines IL-4, IL-5, and IL-10, while decreasing the release of pro-inlammatory cytokines like TNF-α [186,187].…”