127. Decreased functional recovery after SCI in aged mice corresponds with impaired IL-4Rα upregulation on microglia and reduced IL-4-dependent repair

Activated microglia from aged mice are less responsive to anti-inflammatory signals. Indeed, our lab showed that activated microglia from aged mice have impaired upregulation of the receptor for the anti-inflammatory cytokine, interleukin (IL)-4. Impaired upregulation of the IL-4 receptor (IL-4Rα) resulted in reduced sensitivity to the M2 promoting effects of IL-4 ex vivo (i.e., high inducible nitric oxide synthase; low arginase). We hypothesize that this failure to induce IL-4Rα after an inflammatory challenge sensitizes aged mice to a traumatic central nervous system (CNS) injury in which IL-4-dependent repair relies on increased IL-4Rα expression. Here we show that after a spinal cord injury (SCI), microglia from adult, but not aged, mice upregulated surface expression of IL-4Rα. Impaired IL-4Rα upregulation corresponded with reduced functional recovery in aged mice and reduced arginase expression in the spinal cord. Thus, we predict that impaired IL-4Rα upregulation after SCI results in decreased arginase-associated repair including reduced axonal growth. In support of this idea, we used an intracerebroventricular injection model to show that IL-4-mediated arginase expression in microglia is dependent on inflammatory-induced IL-4Rα upregulation. Moreover, in dorsal root ganglion cultures, IL-4-induced neurite growth was only noted in the presence activated microglia (high IL-4Rα). Together, these results indicate that impaired IL-4Rα expression by aged mice after SCI likely leads to reduced IL-4-dependent reparative processes resulting in reduced functional recovery.