Major depression is a prevalent, debilitating disease, yet therapeutic interventions for depression are frequently inadequate. Many clinical and pre-clinical studies have demonstrated that depression is associated with aberrant activation of the inflammatory system, raising the possibility that reducing inflammation may provide antidepressant effects. Using the learned helplessness mouse model, we tested if susceptibility or recovery were affected by deficiency in either of two receptors that initiate inflammatory signaling, Toll-like receptor-4 (TLR4) and TLR2, using knockout male mice. TLR4-/- mice displayed a strong resistance to learned helplessness, confirming that blocking inflammatory signaling through TLR4 provides robust protection against this depression-like behavior. Surprisingly, TLR2-/- mice displayed increased susceptibility to learned helplessness, indicating that TLR2-mediated signaling counteracts susceptibility. TLR2-mediated signaling also promotes recovery, as TLR2-/- mice demonstrated a severe impairment in recovery from learned helplessness. That TLR2 actually protects from learned helplessness was further verified by the finding that administration of the TLR2 agonist Pam3CSK4 reduced susceptibility to learned helplessness. Treatment with Pam3CSK4 also blocked chronic stress-induced impaired sociability and impaired learning in the novel object recognition paradigm, demonstrating that TLR2 stimulation can protect from multiple impairments caused by stress. In summary, these results demonstrate that TLR2-mediated signaling provides a counter-signal to oppose deleterious effects of stress that may be related to depression, and indicate that TLR2 and TLR4 act oppositely to balance mood-relevant responses to stress.

中文翻译：

---

Toll 样受体 2 (TLR2) 缺陷会损害雄性小鼠从抑郁样状态中恢复

重度抑郁症是一种普遍存在的、使人衰弱的疾病，但抑郁症的治疗干预往往不足。许多临床和临床前研究表明，抑郁症与炎症系统的异常激活有关，这增加了减轻炎症可能提供抗抑郁作用的可能性。使用习得性无助小鼠模型，我们使用敲除雄性小鼠测试了易感性或恢复是否受到启动炎症信号传导的两种受体 Toll 样受体 4 (TLR4) 和 TLR2 缺乏的影响。TLR4-/- 小鼠表现出对习得性无助的强烈抵抗力，证实通过 TLR4 阻断炎症信号传导可提供针对这种抑郁样行为的强大保护。出奇，TLR2-/- 小鼠对习得性无助的敏感性增加，表明 TLR2 介导的信号传导抵消了敏感性。TLR2 介导的信号传导也促进恢复，因为 TLR2-/- 小鼠表现出从习得性无助中恢复的严重损害。TLR2 实际上可以防止习得性无助，这一发现进一步证实了 TLR2 激动剂 Pam3CSK4 的给药降低了对习得性无助的易感性。用 Pam3CSK4 治疗还在新的对象识别范式中阻止了慢性压力引起的社交能力受损和学习受损，这表明 TLR2 刺激可以防止由压力引起的多种损伤。总之，