運動改善小鼠週邊發炎與閉鎖性頭部外傷的機制:MKP-1可能扮演的角色

Abstract

Regular exercise is beneficial to systemic immunity and brain functions, e.g., promoting the defense against infectious diseases in the peripheral organs and neuro-inflammatory diseases in the brain. However, the mechanisms are unclear. In the study of peripheral immunity, we hypothesized that chronic exercise upregulated macrophage MKP-1 and thus prevented excessive inflammatory responses. Male C57BL/6 mice were divided into exercise and sedentary groups. The former but not the latter group underwent 8 week treadmill exercise at moderate intensity. Both basal immunity and lipopolysaccharide (LPS)-evoked immune responses were compared between groups. Although basal levels of TNF-andIL-6 were undetectable in the serum of both groups, the exercised mice showed the following immune adaptations in vivo: i) higher basal MKP-1 mRNA level in peritoneal macrophages, ii) lower basal p38 MAPK activity and enhanced MKP-1 immunostaining in macrophages, and iii) lower serum levels of IL-6 and TNF-and less leukocyte infiltration into peritoneal cavity after i.p. administration of LPS. When exposed to LPS in vitro peritoneal macrophages in the exercise group showed i) accelerated MKP-1 protein expression, and ii) low levels of p38 MAPK activity and cytokine secretion. Furthermore, 2 months of deconditioning completely reversed the exercise-enhanced basal MKP-1 immunostaining in macrophages and the exercise-suppressed cytokine secretion under LPS-evoked conditions. In the study of the brain inflammation, we hypothesized that chronic exercise upregulated brain MKP-1 and thus prevented excessive neuroinflammatory responses. We investigated whether a post-impact exercise program was beneficial to ICR mice suffered closed-head injury (CHI), which involves both physical damage of neurons and subsequent neuroinflammation. That is, CHI caused immediately elevated neurological severity score, rapid loss of object recognition memory, and followed by progressive location-dependent brain damages (neuronal loss and microglia activation in the cortex and hippocampus). A moderate exercise paradigm (started 2 d post-impact and lasting for 7 or 14 days) effectively restored the object recognition memory, prevented the progressive neuronal loss and microglia activation. However, the exercise started 9 d post-impact was unable to recover recognition memory deficits. We further tested the possible involvement of brain-derived neurotrophic factor (BDNF) and MAP kinase phosphatase-1 (MKP-1) in the exercise-induced beneficial effects. Exercise partially restored the impact-abolished hippocampal expression of BDNF and MPK-1, while oral administration of triptolide (a synthesis inhibitor of MKP-1 and an antagonist of nuclear factor-κB) before each bout of exercise blocked the exercise-restoring effects of MKP-1 and recognition memory, and the exercise-retarded neuronal loss. Although triptolide treatment alone inhibited microglia activation and maintained the neuron number, it did not recover the injury-hampered recognition memory. Therefore, moderate exercise shortly after CHI reversed the deficits in recognition memory and prevented the progression of brain injury partially by upregulating BDNF and MPK-1. However, the major beneficial effect of exercise-induced MKP-1 in our CHI model was to facilitate neuron repair rather than to suppress neuroinflammation. Take together, although the exercise-upregulated MKP-1 is beneficial to both LPS-evoked inflammation in peripheral organs and CHI-evoked inflammation in the brain, its beneficial effects are attributed to different mechanisms. As expected, MKP-1 prevented excessive immune responses in both models. However, in the CHI model it facilitated neuron repair in the early phase which led to reduced neuroinflammation in the late phase.