Jang In Hwa, Kruglov Victor, Cholensky Stephanie H, Smith Declan M, Carey Anna, Bai Suxia, Nottoli Timothy, Bernlohr David A, Camell Christina D
bioRxiv. 2024 Sep 25:2024.09.23.614375. doi: 10.1101/2024.09.23.614375.
Age-related susceptibility to sepsis and endotoxemia is poorly defined, although hyperactivation of the immune system and the expansion of the visceral adipose as an immunological reservoir are underlying features. Macrophages from older organisms exhibit substantial changes, including chronic NLRP3 inflammasome activation, genomic remodeling and a dysfunctional, amplified inflammatory response upon new exposure to pathogen. However, the mechanisms by which old macrophages maintain their inflammatory phenotype during endotoxemia remains elusive. We previously identified , a TGFβ superfamily cytokine, as a top-regulated gene by age and the NLRP3 inflammasome in adipose tissue macrophages (ATMs). Here, we demonstrate that endotoxemia increases inflammatory (CD11c ) ATMs in a dependent manner in old mice. Lifelong systemic or myeloid-specific deletion of leads to reduced endotoxemia- induced inflammation, with decreased CD11c ATMs and inflammatory cytokines, and protection from hypothermia. Moreover, acute blockade of using JQ1, a BRD4 inhibitor, phenocopies old mice with lifelong deficiency. We show that GDF3 promotes the inflammatory phenotype in ATMs by phosphorylating SMAD2/3. Mechanistically, the differential chromatin landscape of ATMs from old mice with or without myeloid-driven indicates that GDF3- SMAD2/3 signaling axis shifts the chromatin accessibility of ATMs towards an inflammatory state during aging. Furthermore, pharmaceutical inhibition of SMAD3 with a specific inhibitor of SMAD3 (SIS3) mimics deletion. SIS3 reduces endotoxemia-mediated inflammation with fewer CD11c ATMs and less severe hypothermia in old, but not young mice, as well as reduced mortality. In human adipose tissue, age positively correlates with level, while inflammation correlates with pSMAD2/3 level. Overall, these results highlight the importance of GDF3-SMAD2/3 axis in driving inflammation in older organisms and identify this signaling axis as a promising therapeutic target for mitigating endotoxemia-related inflammation in the aged.
尽管免疫系统的过度激活以及作为免疫储存库的内脏脂肪增多是其潜在特征，但年龄相关的败血症和内毒素血症易感性仍未得到充分明确。来自老年生物体的巨噬细胞表现出显著变化，包括慢性NLRP3炎性小体激活、基因组重塑以及再次接触病原体时功能失调且增强的炎症反应。然而，老年巨噬细胞在内毒素血症期间维持其炎症表型的机制仍不清楚。我们之前将一种转化生长因子β（TGFβ）超家族细胞因子，鉴定为脂肪组织巨噬细胞（ATM）中受年龄和NLRP3炎性小体调控的最显著上调基因。在此，我们证明内毒素血症以一种依赖于生长分化因子3（GDF3）的方式增加老年小鼠体内炎性（CD11c +）ATM。终身全身性或髓系特异性缺失GDF3会导致内毒素血症诱导的炎症减轻，CD11c + ATM和炎性细胞因子减少，并能预防体温过低。此外，使用BRD4抑制剂JQ1急性阻断GDF3可模拟终身缺乏GDF3的老年小鼠的情况。我们表明GDF3通过磷酸化SMAD2/3促进ATM中的炎症表型。从机制上讲，来自有或没有髓系驱动的GDF3的老年小鼠的ATM的差异染色质景观表明，GDF3 - SMAD2/3信号轴在衰老过程中将ATM的染色质可及性转变为炎症状态。此外，用SMAD3特异性抑制剂（SIS3）对SMAD3进行药物抑制可模拟GDF3缺失。SIS3可减轻内毒素血症介导的炎症，减少老年（而非年轻）小鼠体内的CD11c + ATM数量，并减轻体温过低的严重程度，还能降低死亡率。在人类脂肪组织中，年龄与GDF3水平呈正相关，而炎症与磷酸化SMAD2/3水平相关。总体而言，这些结果突出了GDF3 - SMAD2/3轴在驱动老年生物体炎症中的重要性，并将该信号轴确定为减轻老年人内毒素血症相关炎症的一个有前景的治疗靶点。
