Neuronal Interleukin-4 as a Modulator of Microglial Pathways and Ischemic Brain Damage

Abstract

After ischemic stroke, various damage-associated molecules are released from the ischemic core and diffuse to the ischemic penumbra, activating microglia and promoting proinflammatory responses that may cause damage to the local tissue. Here we demonstrate using in vivo and in vitro models that, during sublethal ischemia, local neurons rapidly produce interleukin-4 (IL-4), a cytokine with potent anti-inflammatory properties. One such anti-inflammatory property includes its ability to polarize macrophages away from a proinflammatory M1 phenotype to a "healing" M2 phenotype. Using an IL-4 reporter mouse, we demonstrated that IL-4 expression was induced preferentially in neurons in the ischemic penumbra but not in the ischemic core or in brain regions that were spared from ischemia. When added to cultured microglia, IL-4 was able to induce expression of genes typifying the M2 phenotype and peroxisome proliferator activated receptor ␥ (PPAR␥) activation. IL-4 also enhanced expression of the IL-4 receptor on microglia, facilitating a "feedforward" increase in (1) their expression of trophic factors and (2) PPAR␥-dependent phagocytosis of apoptotic neurons. Parenteral administration of IL-4 resulted in augmented brain expression of M2-and PPAR␥-related genes. Furthermore, IL-4 and PPAR␥ agonist administration improved functional recovery in a clinically relevant mouse stroke model, even if administered 24 h after the onset of ischemia. We propose that IL-4 is secreted by ischemic neurons as an endogenous defense mechanism, playing a vital role in the regulation of brain cleanup and repair after stroke. Modulation of IL-4 and its associated pathways could represent a potential target for ischemic stroke treatment.

Interleukin-4 Is Essential for Microglia/Macrophage M2 Polarization and Long-Term Recovery After Cerebral Ischemia

“…16 In addition, a recent study demonstrated that injured neurons may release IL-4 at acute stages of stroke. 17 These results suggest that increased signaling through the IL-4 receptor may mitigate the inflammatory environment after stroke and lay the groundwork for recovery of neural function. Consistent with this hypothesis, we demonstrated that IL-4 deficiency significantly impairs sensorimotor and cognitive performance in two models of stroke, whereas IL-4 supplementation improves long-term functional outcomes after brain ischemia.…”

Role of neuroinflammation in ischemic stroke

“…IL-4 is known to regulate a variety of immune and inflammatory responses, including T cell differentiation and IgE class in B cells. [114] IL-4 is primary produced by TH2 cells. [115] During CD4+ cellular activation, cytokines are through T cell receptor mediated signaling and co-stimulation.…”

Lack of functional P2X7 receptor aggravates brain edema development after middle cerebral artery occlusion

“…The presence of M2 microglia favors tissue repair and studies involving mice lacking IL-4, which evokes transition towards the M2 phenotype, have shown that the outcome worsens in absence of M2 microglia [33]. In a recent study, it has been shown that IL-4 expression is enhanced in the penumbra of infarcted tissue, where it reaches its peak during the first 24 h [34]. Even though data regarding microglia is not available, it has been proven that M2 macrophages do express P2X7 [35].…”