Age-related differences in cellular and molecular profiles of inflammatory responses after spinal cord injury

Previous experimental and clinical studies have suggested that the behavioral and pathological outcomes of spinal cord injury (SCI) are affected by the individual's age at the time of injury. However, the underlying mechanism responsible for these differences remains elusive because it is difficult to match injuries of similar severities between young and adult animals due to differences in the sizes of their respective spinal cords. In this study, the spinal cord size-matched young (4-week-old) and adult (10-week-old) mice were compared to evaluate their locomotor functions and inflammatory cellular/molecular responses after standardized contusion SCI. During the acute phase of SCI, young mice showed better functional recovery and lower pro-inflammatory cytokines/chemokines compared to adult mice. Flow-cytometric analysis revealed that the time courses of leukocyte infiltration were comparable between both groups, while the number of infiltrating neutrophils significantly decreased from 6 h after SCI in young mice. By combining flow-cytometric isolation and gene expression analysis of each inflammatory cell fraction, we found that microglial cells immediately initiate the production of several cytokines in response to SCI, which serve as major sources of IL-6, TNFa, and CXCL1 in injured spinal cord. Interestingly, the secretion of pro-inflammatory cytokines/chemokines but not anti-inflammatory cytokines by microglia was significantly lower in young mice compared to that in adult mice at 3 h after SCI, which will be attributed to the attenuation of the subsequent neutrophil infiltration. These results highlight age-related differences in pro-inflammatory properties of microglial cells that contribute to the amplification of detrimental inflammatory responses after SCI.