IL-4 Signaling Drives a Unique Arginase +/IL-1β+ Microglia Phenotype and Recruits Macrophages to the Inflammatory CNS: Consequences of Age-Related Deficits in IL-4Rα after Traumatic Spinal Cord Injury

Alternative activation of microglia/ macrophages (M2a) by interleukin (IL)-4 is purported to support intrinsic growth and repair processes after CNS injury. Nonetheless, alternative activation of microglia is poorly understood in vivo, particularly in the context of inflammation, injury, and aging. Here, we show that aged mice (18 -19 months) had reduced functional recovery after spinal cord injury (SCI) associated with impaired induction of IL-4 receptor alpha (IL-4R alpha) on microglia. The failure to successfully promote an IL-4/ IL-4R alpha response in aged mice resulted in attenuated arginase (M2a associated), IL-1, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4R macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4R beta expression and reduced arginase, IL-1, and CCL2 expression was confirmed using adult IL-4R beta knock-out (IL-4R alpha(KO)) mice. To better understand IL-4R -mediated regulation of active microglia, a series of studies was completed in mice that were peripherally injected with lipopolysaccharide and later provided IL-4 by intracerebroventricular infusion. These immune-based studies demonstrate that inflammatoryinduced IL-4R alpha upregulation on microglia was required for the induction of arginase by IL-4. In addition, IL-4-mediated reprogramming of active microglia enhanced neurite growth ex vivo and increased inflammatory gene expression (i. e., IL-1 beta and CCL2) and the corresponding recruitment of CCR2 alpha / IL-4R -/ arginase myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase alpha/IL-1 beta+) that augmented neurite growth and enhanced recruitment of peripheral IL-4R alpha+ myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI.