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

Ashley M. Fenn, Jodie C.E. Hall, John C. Gensel, Phillip G. Popovich, Jonathan P. Godbout

Research output: Contribution to journalArticlepeer-review

136 Scopus citations

Abstract

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 α (IL-4Rα) on microglia. The failure to successfully promote an IL-4/IL-4Rα response in aged mice resulted in attenuated arginase (M2a associated), IL-1β, and chemokine ligand 2 (CCL2) expression, and diminished recruitment of IL-4Rα+ macrophages to the injured spinal cord. Furthermore, the link between reduced IL-4Rα expression and reduced arginase, IL-1β, and CCL2 expression was confirmed using adult IL-4Rα knock-out (IL-4RαKO) mice. To better understand IL-4Rα-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 inflammatory-induced IL-4Rα 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-1β and CCL2) and the corresponding recruitment of CCR2+/IL-4Rα+/arginase+ myeloid cells in vivo. IL-4 reprogrammed active microglia to a unique and previously unreported phenotype (arginase+/IL-1β+) that augmented neurite growth and enhanced recruitment of peripheral IL-4Rα+ myeloid cells to the CNS. Moreover, this key signaling cascade was impaired with age corresponding with reduced functional recovery after SCI.

Original languageEnglish
Pages (from-to)8904-8917
Number of pages14
JournalJournal of Neuroscience
Volume34
Issue number26
DOIs
StatePublished - 2014

Keywords

  • Advanced age
  • IL-4
  • Inflammation
  • M2a
  • Microglia
  • Spinal cord injury

ASJC Scopus subject areas

  • Neuroscience (all)

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