IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function.
IL-15 Enables Septic Shock by Maintaining NK Cell Integrity and Function.
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IL-15通过维持NK细胞完整性和功能来启用败血性休克。
DOI：
10.4049/jimmunol.1601486
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Sherwood ER
中科院分区：
文献类型：
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作者：
Guo Y;Luan L;Patil NK;Wang J;Bohannon JK;Rabacal W;Fensterheim BA;Hernandez A;Sherwood ER
白细胞介素-15（IL-15）对于自然杀伤（NK）和记忆（m）CD 8 + T细胞的发育和分化是必需的。我们的实验室先前表明，NK和CD 8 + T淋巴细胞促进脓毒性休克的病理生物学。然而，在脓毒症过程中调节NK和CD 8 + T淋巴细胞功能的因素还没有得到很好的表征。我们假设IL-15通过维持NK和mCD 8 + T细胞的完整性促进脓毒症的发病机制。为了检验我们的假设，在IL-15缺陷（IL-15 KO）小鼠中评估脓毒症的发病机制。IL-15 KO小鼠在盲肠结扎穿孔（CLP）或内毒素诱导的休克引起的脓毒性休克期间表现出存活率提高、体温降低和促炎细胞因子产生减少。用IL-15超激动剂（IL-15 SA、IL-15/IL-15 R α复合物）处理可再生NK和mCD 8 + T细胞，并重新确立了IL-15 KO小鼠在脓毒性休克期间的死亡率。阻止NK细胞再生减弱了IL-15 SA引起的死亡率恢复。如果在脓毒性攻击之前立即给予，IL-15中和IgG M96不能防止脓毒性休克。然而，如果在脓毒症攻毒前4天给予M96，则会导致NK细胞耗竭，并提供保护。IL-15 SA处理放大了内毒素休克，而NK细胞或IFNγ耗竭可防止内毒素休克。当在脓毒症发作后给予IL-15 SA治疗时，IL-15 SA治疗还加重了CLP引起的脓毒性休克。总之，内源性IL-15并不直接增加脓毒症的发病机制，但通过维持NK细胞的数量和完整性使脓毒性休克的发展成为可能。外源性IL-15通过激活NK细胞和促进IFNγ产生而加重脓毒症的严重程度。
Interleukin-15 (IL-15) is essential for development and differentiation of natural killer (NK) and memory (m)CD8+ T cells. Our lab previously showed that NK and CD8+ T lymphocytes facilitate the pathobiology of septic shock. However, factors that regulate NK and CD8+ T lymphocyte functions during sepsis are not well characterized. We hypothesized that IL-15 promotes the pathogenesis of sepsis by maintaining NK and mCD8+ T cell integrity. To test our hypothesis, the pathogenesis of sepsis was assessed in IL-15-deficient (IL-15 KO) mice. IL-15 KO mice showed improved survival, attenuated hypothermia, and less pro-inflammatory cytokine production during septic shock caused by cecal ligation and puncture (CLP) or endotoxin-induced shock. Treatment with IL-15 superagonist (IL-15 SA, IL-15/IL-15Rα complex) regenerated NK and mCD8+ T cells and re-established mortality of IL-15 KO mice during septic shock. Preventing NK cell regeneration attenuated the restoration of mortality caused by IL-15 SA. If given immediately prior to septic challenge, IL-15 neutralizing IgG M96 failed to protect against septic shock. However, M96 caused NK cell depletion if given 4 days prior to septic challenge and conferred protection. IL-15 SA treatment amplified endotoxin shock, which was prevented by NK cell or IFNγ depletion. IL-15 SA treatment also exacerbated septic shock caused by CLP when given after the onset of sepsis. In conclusion, endogenous IL-15 doesn’t directly augment the pathogenesis of sepsis but enables the development of septic shock by maintaining NK cell numbers and integrity. Exogenous IL-15 exacerbates the severity of sepsis by activating NK cells and facilitating IFNγ production.