Interleukin-1 Mediates Ischemic Brain Injury via Induction of IL-17A in γδ T Cells and CXCL1 in Astrocytes.

As a prototypical proinflammatory cytokine, interleukin-1 (IL-1) exacerbates the early post-stroke inflammation, whereas its neutralization is protective. To further investigate the underlying cell-type-specific IL-1 effects, we subjected IL-1 (α/ß) knockout (Il1-/-) and wildtype (WT) littermate mice to permanent middle cerebral artery occlusion (pMCAO) and assessed immune cell infiltration and cytokine production in the ischemic hemisphere by flow cytometry 24 h and 72 h after stroke. Il1-/- mice showed smaller infarcts and reduced neutrophil infiltration into the ischemic brain. We identified γδ T cells and astrocytes as target cells of IL-1 signaling-mediated neutrophil recruitment. First, IL-1-induced IL-17A production in γδ T cells in vivo, and IL-17A enhanced the expression of the main neutrophil attracting chemokine CXCL1 by astrocytes in the presence of tumor necrosis factor (TNF) in vitro. Second, IL-1 itself was a potent activator of astrocytic CXCL1 production in vitro. By employing a novel FACS sorting strategy for the acute isolation of astrocytes from ischemic brains, we confirmed that IL-1 is pivotal for Cxcl1 upregulation in astrocytes in vivo. Our results underscore the pleiotropic effects of IL-1 on immune and non-immune cells within the CNS to mount and amplify the post-stroke inflammatory response.

Neuronal Ablation of IKK2 Decreases Lesion Size and Improves Functional Outcome after Spinal Cord Injury in Mice.

Nuclear factor-kappa B (NF-κB) is a key modulator of inflammation and secondary injury responses in neurodegenerative disease, including spinal cord injury (SCI). Inhibition of astroglial NF-κB reduces inflammation, enhances oligodendrogenesis and improves functional recovery after SCI, however the contribution of neuronal NF-κB to secondary inflammatory responses following SCI has yet to be investigated. We demonstrate that conditional ablation of IKK2 in Synapsin 1-expressing neurons in mice (Syn1creIKK2fl/fl) reduces activation of the classical NF-κB signaling pathway, resulting in impaired motor function and altered memory retention under naïve conditions. Following induction of a moderate SCI phosphorylated NF-κB levels decreased in the spinal cord of Syn1creIKK2fl/fl mice compared to controls, resulting in improvement in functional recovery. Histologically, Syn1creIKK2fl/fl mice exhibited reduced lesion volume but comparable microglial/leukocyte responses after SCI. In parallel, interleukin (IL)-1ß expression was significantly decreased within the lesioned spinal cord, whereas IL-5, IL-6, IL-10, tumor necrosis factor (TNF) and chemokine (C-X-C motif) ligand 1 were unchanged compared to control mice. We conclude that conditional ablation of IKK2 in neurons, resulting in reduced neuronal NF-B signaling, and lead to protective effects after SCI and propose the neuronal classical NF-κB pathway as a potential target for the development of new therapeutic, neuroprotective strategies for SCI.