Department of Health, Exercise and Sports Sciences, University of New Mexico, Albuquerque, New Mexico, United States.
Institute for Exercise and Environmental Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, United States.
J Appl Physiol (1985). 2024 Jan 1;136(1):33-42. doi: 10.1152/japplphysiol.00626.2023. Epub 2023 Nov 23.
Exercise in hypoxia increases immune responses compared with normoxic exercise, and while Toll-like receptor 4 (TLR4) is implicated in these responses, its regulation remains undefined. The purpose of this study was to ) investigate TLR4 regulation during workload-matched endurance exercise in normoxic and hypoxic conditions in vivo and ) determine the independent effects of hypoxia and muscle contractions on TLR4 expression in vitro. Eight recreationally active men cycled for 1 h at 65% of their V̇o in normoxia (630 mmHg) and in hypobaric hypoxia (440 mmHg). Exercise in normoxia decreased TLR4 expressed on peripheral blood mononuclear cells (PBMCs), had no effect on the expression of inhibitor of κBα (IκBα), and increased the concentration of soluble TLR4 (sTLR4) in circulation. In contrast, exercise in hypoxia decreased the expression of TLR4 and IκBα in PBMCs, and sTLR4 in circulation. Markers of physiological stress were higher during exercise in hypoxia, correlating with markers of intestinal barrier damage, circulating lipopolysaccharides (LPS), and a concurrent decrease in circulating sTLR4, suggesting heightened TLR4 activation, internalization, and degradation in response to escalating physiological strain. In vitro, both hypoxia and myotube contractions independently, and in combination, reduced TLR4 expressed on C2C12 myotubes, and these effects were dependent on hypoxia-inducible factor 1 (HIF-1). In summary, the regulation of TLR4 varies depending on the physiological stress during exercise. To our knowledge, our study provides the first evidence of exercise-induced effects on sTLR4 in vivo and highlights the essential role of HIF-1 in the reduction of TLR4 during contraction and hypoxia in vitro. We provide the first evidence of exercise affecting soluble Toll-like receptor 4 (sTLR4), a TLR4 ligand decoy receptor. We found that the degree of exercise-induced physiological stress influences TLR4 regulation on peripheral blood mononuclear cells (PBMCs). Moderate-intensity exercise reduces PBMC TLR4 and increases circulating sTLR4. Conversely, workload-matched exercise in hypoxia induces greater physiological stress, intestinal barrier damage, circulating lipopolysaccharides, and reduces both TLR4 and sTLR4, suggesting heightened TLR4 activation, internalization, and degradation under increased strain.
在低氧环境下运动比在常氧环境下运动更能增强免疫反应，而 Toll 样受体 4（TLR4）与这些反应有关，但它的调节仍不清楚。本研究的目的是：i）研究在常氧和低氧条件下，进行等负荷耐力运动时 TLR4 的调节；ii）确定低氧和肌肉收缩对体外 TLR4 表达的独立影响。8 名有规律运动的男性以 65%的最大摄氧量（V̇o）在常氧（630mmHg）和低气压缺氧（440mmHg）下进行 1 小时的自行车运动。常氧运动降低了外周血单核细胞（PBMCs）上 TLR4 的表达，对 IκBα 的表达没有影响，并增加了循环中可溶性 TLR4（sTLR4）的浓度。相比之下，低氧运动降低了 PBMCs 中 TLR4 和 IκBα 的表达，以及循环中 sTLR4 的浓度。低氧运动时生理应激标志物升高，与肠道屏障损伤标志物、循环内毒素（LPS）和循环中 sTLR4 同时降低相关，提示 TLR4 在应对不断增加的生理应激时，激活、内化和降解增加。在体外，低氧和肌管收缩都可以独立地降低 C2C12 肌管上 TLR4 的表达，并且这些作用依赖于缺氧诱导因子 1（HIF-1）。总之，TLR4 的调节取决于运动期间的生理应激程度。据我们所知，我们的研究首次提供了运动对体内 sTLR4 影响的证据，并强调了 HIF-1 在体外收缩和低氧条件下降低 TLR4 表达中的重要作用。我们提供了运动影响可溶性 Toll 样受体 4（sTLR4）的第一个证据，sTLR4 是 TLR4 配体的诱饵受体。我们发现，运动引起的生理应激程度影响外周血单核细胞（PBMCs）上 TLR4 的调节。中等强度的运动降低了 PBMC TLR4 并增加了循环中的 sTLR4。相反，在低氧环境下进行等负荷运动则会引起更大的生理应激、肠道屏障损伤、循环内毒素，并降低 TLR4 和 sTLR4，这表明在高压力下，TLR4 的激活、内化和降解增强。
