Cao Shan, Schnelzer Anne, Hannemann Nicole, Schett Georg, Soulat Didier, Bozec Aline
Department of Internal Medicine 3, Rheumatology and Immunology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany.
Institute of Regenerative Medicine and Biotherapies (IRMB), University of Montpellier, INSERM U1183, Montpellier, France.
Front Immunol. 2021 Oct 12;12:701675. doi: 10.3389/fimmu.2021.701675. eCollection 2021.
Sepsis is a life-threatening condition characterized by excessive inflammation in its early phase. This is followed by an aberrant resolution phase associated to a prolonged period of immune suppression that can ultimately lead to multiple organ dysfunctions. This immunosuppression can be mediated by the functional reprogramming of gene transcription in monocytes/macrophages in response to prolonged lipopolysaccharide (LPS) exposure. Surprisingly, there is no report on the role of AP-1 transcription factors in this reprogramming process. Herein, we used the endotoxin tolerance model on murine bone marrow-derived macrophages in which tolerant cells stimulated twice with LPS were compared to naïve cells stimulated once. Out of all AP-1 transcription factors tested, gene stood out because of its unique regulation in tolerized cells. Moreover, we could correlate FRA-1 expression to the expression of an essential anti-inflammatory molecule involved in sepsis response, Lipocalin 2 aka NGAL. Identical results were obtained in human PBMC following the endotoxin tolerance model. When using FRA-1 deficient macrophages, we could confirm that FRA-1 regulates NGAL expression during the tolerant state. Interestingly, ChIP-seq and ChIP-qPCR revealed the binding of FRA-1 on promoter after LPS stimulation in these cells. Finally, we used an septic model of consecutive injection of LPS, in which the second stimulation is performed before the resolution of inflammation, in wild type and FRA-1 deficient mice. NGAL secretion was elevated in lung, spleen and serum of wild type tolerant mice, whereas it was significantly lower in tolerant FRA-1 deficient mice. Moreover, an increased inflammatory state likely dependent of the low level of NGAL was observed in these FRA-1 deficient mice. This was characterized by an increase of neutrophil infiltration in lung and an increase of apoptotic follicular cells in spleen. This suggests that FRA-1 expression supports resolution of inflammation in this model. Collectively, our data indicate that FRA-1 is involved in myeloid cell tolerance responses by mediating the functional reprogramming of transcription in response to prolonged LPS exposure. In conclusion, FRA-1 may have a protective role in the tolerance response of sepsis through the regulation of NGAL, leading to resolution of inflammation.
脓毒症是一种危及生命的病症，其早期特征为过度炎症反应。随后是一个异常的消退期，与长时间的免疫抑制相关，最终可导致多器官功能障碍。这种免疫抑制可由单核细胞/巨噬细胞中基因转录的功能重编程介导，这是对长时间暴露于脂多糖（LPS）的反应。令人惊讶的是，尚无关于AP - 1转录因子在这一重编程过程中作用的报道。在此，我们在小鼠骨髓来源的巨噬细胞上使用内毒素耐受模型，将用LPS刺激两次的耐受细胞与仅刺激一次的未处理细胞进行比较。在所有测试的AP - 1转录因子中， 基因脱颖而出，因为其在耐受细胞中有独特的调控方式。此外，我们能够将FRA - 1的表达与脓毒症反应中一种重要的抗炎分子——脂钙蛋白2（又名NGAL）的表达相关联。在内毒素耐受模型后的人外周血单核细胞中也获得了相同的结果。当使用FRA - 1缺陷型巨噬细胞时，我们可以证实FRA - 1在耐受状态下调节NGAL的表达。有趣的是，ChIP - seq和ChIP - qPCR显示在这些细胞中LPS刺激后FRA - 1与 启动子结合。最后，我们在野生型和FRA - 1缺陷型小鼠中使用连续注射LPS的脓毒症模型，其中第二次刺激在炎症消退前进行。野生型耐受小鼠的肺、脾和血清中NGAL分泌升高，而FRA - 1缺陷型耐受小鼠中的NGAL分泌显著降低。此外，在这些FRA - 1缺陷型小鼠中观察到炎症状态增加，这可能与低水平的NGAL有关。其特征为肺中嗜中性粒细胞浸润增加以及脾中凋亡滤泡细胞增加。这表明在该模型中FRA - 1的表达有助于炎症的消退。总体而言，我们的数据表明FRA - 1通过介导对长时间LPS暴露的反应中 转录的功能重编程参与髓样细胞耐受反应。总之，FRA - 1可能通过调节NGAL在脓毒症的耐受反应中发挥保护作用，从而导致炎症消退。
