Department of Dermatology, Shanghai Skin Disease Hospital, Institute of Psoriasis, Tongji University, Shanghai, China.
Eye Institute and Department of Ophthalmology, Eye & ENT Hospital, Fudan University, NHC Key Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai Key Laboratory of Visual Impairment and Restoration, Shanghai, China.
Front Immunol. 2021 Sep 8;12:739514. doi: 10.3389/fimmu.2021.739514. eCollection 2021.
Generalized pustular psoriasis (GPP), the most grievous variant of psoriasis, is featured by dysregulated systemic inflammatory response. The cellular and molecular basis of GPP is poorly understood. Blood monocytes are key players of host defense and producers of inflammatory cytokines including IL-1β. How the immune response of monocytes is affected by metabolic internal environment in GPP remains unclear. Here, we performed a metabolomic and functional investigation of GPP serum and monocytes. We demonstrated a significant increase in IL-1β production from GPP monocytes. In GPP circulation, serum amyloid A (SAA), an acute-phase reactant, was dramatically increased, which induced the release of IL-1β from monocytes in a NLRP3-dependent manner. Using metabolomic analysis, we showed that GPP serum exhibited an amino acid starvation signature, with glycine, histidine, asparagine, methionine, threonine, lysine, valine, isoleucine, tryptophan, tyrosine, alanine, proline, taurine and cystathionine being markedly downregulated. In functional assay, under amino acid starvation condition, SAA-stimulated mature IL-1β secretion was suppressed. Mechanistically, at post-transcriptional level, amino acid starvation inhibited the SAA-mediated reactive oxygen species (ROS) formation and NLRP3 inflammasome activation. Moreover, the immune-modulatory effect of amino acid starvation was blocked by silencing general control nonderepressible 2 kinase (GCN2), suggesting the involvement of amino acid response (AAR) pathway. Collectively, our results suggested that decreased serum amino acids in GPP blunted the innate immune response in blood monocytes through AAR pathway, serving as a feedback mechanism preventing excessive inflammation in GPP.
全身性脓疱型银屑病（GPP）是银屑病最严重的一种类型，其特征是系统性炎症反应失调。GPP 的细胞和分子基础尚未完全清楚。血液单核细胞是宿主防御的关键参与者，也是包括白细胞介素-1β（IL-1β）在内的炎症细胞因子的产生者。代谢内环境如何影响 GPP 中单核细胞的免疫反应尚不清楚。在这里，我们对 GPP 血清和单核细胞进行了代谢组学和功能研究。我们证明了 GPP 单核细胞产生的 IL-1β 显著增加。在 GPP 循环中，血清淀粉样蛋白 A（SAA）作为一种急性期反应物显著增加，以 NLRP3 依赖的方式诱导单核细胞释放 IL-1β。通过代谢组学分析，我们发现 GPP 血清表现出氨基酸饥饿特征，甘氨酸、组氨酸、天冬酰胺、蛋氨酸、苏氨酸、赖氨酸、缬氨酸、异亮氨酸、色氨酸、酪氨酸、丙氨酸、脯氨酸、牛磺酸和胱硫醚明显下调。在功能测定中，在氨基酸饥饿条件下，SAA 刺激的成熟 IL-1β 分泌受到抑制。在机制上，在转录后水平上，氨基酸饥饿抑制了 SAA 介导的活性氧（ROS）形成和 NLRP3 炎性小体激活。此外，通过沉默普遍控制非阻遏 2 激酶（GCN2），阻断了氨基酸饥饿的免疫调节作用，表明涉及氨基酸反应（AAR）途径。总之，我们的结果表明，GPP 中血清氨基酸的减少通过 AAR 途径削弱了血液单核细胞的固有免疫反应，作为一种反馈机制防止 GPP 中过度炎症。
