Talk abstracts

Talk on Wednesday 09:30-09:45am submitted by Ashley Fenn

Impaired upregulation of IL-4Rα on active microglia of aged mice results in reduced repair and increased functional deficits after spinal cord injury

Ashley M. Fenn (Neuroscience, The Ohio State University), Jodie C. Hall (Neuroscience, The Ohio State University), John C. Gensel (Physiology, University of Kentucky), Phillip G. Popovich (Neuroscience, The Ohio State University), Jonathan P. Godbout (Neuroscience, The Ohio State University)

Abstract:
Morbidity and mortality that accompanies spinal cord injury (SCI) is exacerbated nearly 9-fold in older people. A possible explanation for worse outcome in the aged is a deficiency in reparative processes by interleukin (IL)-4. Indeed, our lab has shown that inflammatory-induced upregulation of the receptor for IL-4 (IL-4Rα) is impaired on active microglia from aged mice resulting in an insensitivity to IL-4 and a failure to shift to a reparative phenotype (e.g., increased arginase). Thus, the objectives of this study were to determine the relationship between impaired IL-4Rα upregulation on microglia of aged mice and the induction of microglial-specific arginase, gross tissue sparing, and functional recovery after a mid-thoracic SCI. Adult and aged mice received a mid-thoracic SCI and IL-4Rα protein expression on microglia was determined. We show novel data that SCI induced high levels of IL-4Rα protein expression on microglia of adult, but not aged mice. Moreover, 7 d after injury arginase protein expression was reduced in microglia/macrophages of aged mice, despite a maintained or increased number of microglia/macrophages. This age-associated reduction in reparative markers and increased inflammatory cell accumulation coincided with increased lesion length in aged mice and worsened functional recovery. To identify a direct connection between inflammatory-associated IL-4Rα upregulation on microglia, IL-4-dependent arginase expression, and IL-4 promoted neuronal growth, a series of intracerebroventricular (icv) injection studies were performed. Adult mice were implanted with an indwelling cannula into the lateral ventricle, injected peripherally with lipopolysaccharide, and 1 h later received an icv injection of vehicle or IL-4. We report that IL-4-dependent arginase expression was restricted to microglia and only observed in the presence of IL-4Rα upregulation (i.e., LPS injection). Furthermore, only active microglia with increased arginase expression promoted significant neurite growth in a neuronal co-culture system. Collectively, these data support our central hypothesis that impaired SCI-induced IL-4Rα upregulation on active microglia of aged mice prevents IL-4-dependent reparative processes causing increased tissue damage and worse functional outcome.

Keywords: CNS injury, Aging, Repair