Department of Neurobiology, GELIFES, University of Groningen, the Netherlands.
Department of Internal Medicine II, Division of Molecular Internal Medicine, University Hospital Wurzburg, Germany.
Brain Behav Immun. 2021 Mar;93:156-171. doi: 10.1016/j.bbi.2021.01.001. Epub 2021 Jan 12.
Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI.
Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation.
MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior.
Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed.
心肌梗死（MI）合并抑郁症会使预后恶化。虽然肿瘤坏死因子-α（TNF）被认为在这两种情况下都发挥作用，但 TNF 抑制的治疗潜力却令人失望。TNF 激活两种受体，TNFR1 和 TNFR2，与相反的作用相关。因此，与非特异性 TNF 抑制相比，用特异性 TNF 受体干扰进行抗炎治疗，观察其对 MI 小鼠的心脏、（神经）炎症、大脑和行为的影响。
雄性 C57BL/6 小鼠接受 MI 或假手术。MI 后 1 小时，MI 小鼠随机分为接受 Enbrel 进行非特异性 TNF 抑制、特异性 TNFR1 拮抗剂或特异性 TNFR2 激动剂治疗，直至方案结束。对照假手术和 MI 小鼠接受生理盐水。手术后第 10-14 天进行行为评估。手术后第 18 天，测量心脏功能，然后处死小鼠。收集血液和组织样本，分析（神经）炎症。
MI 小鼠表现出左心室功能障碍，无心力衰竭、（神经）炎症或抑郁样行为。两种受体特异性干预措施，但不是 Enbrel，都使 MI 后早期死亡率增加了一倍。TNFR2 激动剂治疗改善了左心室功能，并导致小胶质细胞过度分支，对抑郁样行为没有影响。相比之下，TNFR1 拮抗剂治疗与（神经）炎症增强相关：更多的血浆嗜酸性粒细胞和单核细胞；血浆 Lcn2 和海马小胶质细胞和星形胶质细胞激活增加。此外，基础心率增加，β-肾上腺素能反应性降低表明交感神经激活，同时伴有旷场试验中探索行为减少。Enbrel 既不影响神经炎症，也不影响行为。
早期受体干预而非非特异性 TNF 抑制会增加死亡率。除了这种不良影响外，TNFR2 刺激后的总体有益作用，而不是 TNFR1 抑制的不利影响，使得 TNFR2 刺激优于 MI 合并抑郁症的非特异性 TNF 抑制。然而，需要进一步的研究来确定最佳的治疗时机和剂量。
