IL-33 causes thermogenic failure in aging by expanding dysfunctional adipose ILC2 [bulk rnaseq]

Aging impairs the integrated immunometabolic responses which have evolved to maintain core body temperature in homeotherms to survive cold-stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response but how adipose tissue-resident cells instigate thermogenic failure in the aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and increased cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2 are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2 during aging drive thermogenic failure. Overall design: IL-33 was given by ip injection daily for 5 consecutive days to adult and old mice. Then, mice were rested for 6 additional weeks prior to tissue collection and ILC2 isolation from VAT.

衰老会损害整合性免疫代谢应答，该应答是恒温动物为在寒冷应激、感染及饮食限制条件下存活而演化出的维持核心体温的适应性机制。脂肪组织炎症可调控产热应激应答，但目前学界尚未明确衰老个体内的脂肪组织驻留细胞如何引发产热衰竭。本研究阐明了脂肪驻留免疫系统的异常改变，并发现2型先天淋巴样细胞（type 2 innate lymphoid cells，ILC2）在衰老进程中发生缺失。通过补充IL-33将衰老小鼠体内的ILC2数量恢复至成年小鼠水平，不仅未能挽救衰老小鼠的代谢损伤，反而加剧了寒冷诱导的致死率。转录组学分析揭示了衰老ILC2存在内在缺陷，而过继转移成年小鼠的ILC2足以保护衰老小鼠抵御寒冷应激。因此，衰老过程中脂肪组织ILC2的功能缺陷是驱动产热衰竭的核心因素。实验设计：对成年与衰老小鼠连续5天每日腹腔注射（intraperitoneal, ip）IL-33。随后让小鼠静置6周，之后收集组织并从内脏脂肪组织（visceral adipose tissue, VAT）中分离ILC2。