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Within hours after stroke, potentially cytotoxic pro-inflammatory mediators are elevated within the brain; thus, one potential therapeutic strategy is to reduce them and skew the brain toward an anti-inflammatory state. Because interleukin-4 (IL-4) treatment induces an anti-inflammatory, “alternative-activation” state in microglia and macrophages in vitro, we tested the hypothesis that early supplementation of the brain with IL-4 can shift it toward an anti-inflammatory state and reduce damage after transient focal ischemia. Adult male rat striata were injected with endothelin-1, with or without co-injection of IL-4. Inflammation, glial responses and damage to neurons and white matter were quantified from 1 to 7 days later. At 1 day, IL-4 treatment increased striatal expression of several anti-inflammatory markers (ARG1, CCL22, CD163, PPARγ), increased phagocytic (Iba1-positive, CD68-positive) microglia/macrophages, and increased VEGF-A-positive infiltrating neutrophils in the infarcts. At 7 days, there was evidence of sustained, propagating responses. IL-4 increased CD206, CD200R1, IL-4Rα, STAT6, PPARγ, CD11b, and TLR2 expression and increased microglia/macrophages in the infarct and astrogliosis outside the infarct. Neurodegeneration and myelin damage were not reduced, however. The sustained immune and glial responses when resolution and repair processes have begun warrant further studies of IL-4 treatment regimens and long-term outcomes.

The progression of white matter damage after ischemic and hemorrhagic strokes can exacerbate the initial injury, but little is known about the processes involved. We show that the antiadhesive matricellular glycoprotein SC1 is a novel early marker of white matter damage in 3 models of acute injury in the rat striatum: transient focal ischemia, intracerebral hemorrhage, and a needle penetration wound. SC1 was restricted to the damaged portions of axon bundles that bordered stroke lesions in young-adult and aged rats. SC1 peaked at 1 and 3 days after intracerebral hemorrhage and at 7 days after ischemia. The SC1-positive bundles usually expressed degraded myelin basic protein and amyloid precursor protein, a marker of axonal injury. At the hematoma edge, SC1 was seen in a few axon bundles that retained myelin basic protein staining. In these bundles, punctate SC1 staining filled individual axons, extended beyond a core of pan-axonal neurofilament and NF200 and was inside or overlapped with myelin basic protein staining when it was present. Aged rats had less SC1 (and amyloid precursor protein) after both types of stroke, suggesting a reduced axonal response. SC1 also labeled amyloid precursor protein-positive axon bundles along the needle penetration tract of saline-injected rats; thus, SC1 appears to characterize damaged striatal white matter damage after multiple types of injury.