Soták Matúš, Clark Madison, Suur Bianca E, Börgeson Emma
Department of Clinical Immunology and Transfusion Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
Steno Diabetes Center Aarhus, Aarhus University Hospital, Aarhus, Denmark.
Nat Rev Endocrinol. 2025 Jan;21(1):45-61. doi: 10.1038/s41574-024-01047-y. Epub 2024 Oct 24.
Inflammation is an essential physiological defence mechanism, but prolonged or excessive inflammation can cause disease. Indeed, unresolved systemic and adipose tissue inflammation drives obesity-related cardiovascular disease and type 2 diabetes mellitus. Drugs targeting pro-inflammatory cytokine pathways or inflammasome activation have been approved for clinical use for the past two decades. However, potentially serious adverse effects, such as drug-induced weight gain and increased susceptibility to infections, prevented their wider clinical implementation. Furthermore, these drugs do not modulate the resolution phase of inflammation. This phase is an active process orchestrated by specialized pro-resolving mediators, such as lipoxins, and other endogenous resolution mechanisms. Pro-resolving mediators mitigate inflammation and development of obesity-related disease, for instance, alleviating insulin resistance and atherosclerosis in experimental disease models, so mechanisms to modulate their activity are, therefore, of great therapeutic interest. Here, we review current clinical attempts to either target pro-inflammatory mediators (IL-1β, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, tumour necrosis factor (TNF) and IL-6) or utilize endogenous resolution pathways to reduce obesity-related inflammation and improve cardiometabolic outcomes. A remaining challenge in the field is to establish more precise biomarkers that can differentiate between acute and chronic inflammation and to assess the functionality of individual leukocyte populations. Such advancements would improve the monitoring of drug effects and support personalized treatment strategies that battle obesity-related inflammation and cardiometabolic disease.
炎症是一种重要的生理防御机制，但炎症持续时间过长或过度会引发疾病。事实上，未解决的全身性和脂肪组织炎症会导致肥胖相关的心血管疾病和2型糖尿病。在过去二十年中，针对促炎细胞因子途径或炎性小体激活的药物已获批用于临床。然而，潜在的严重不良反应，如药物诱导的体重增加和感染易感性增加，阻碍了它们在临床上的更广泛应用。此外，这些药物不会调节炎症的消退阶段。这个阶段是一个由专门的促消退介质（如脂氧素）和其他内源性消退机制精心编排的活跃过程。促消退介质可减轻炎症和肥胖相关疾病的发展，例如，在实验性疾病模型中减轻胰岛素抵抗和动脉粥样硬化，因此，调节其活性的机制具有极大的治疗意义。在这里，我们综述了目前针对促炎介质（白细胞介素-1β、含核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）炎性小体、肿瘤坏死因子（TNF）和白细胞介素-6）或利用内源性消退途径来减少肥胖相关炎症并改善心脏代谢结局的临床尝试。该领域仍然面临的一个挑战是建立更精确的生物标志物，以区分急性炎症和慢性炎症，并评估单个白细胞群体的功能。这些进展将改善对药物效果的监测，并支持对抗肥胖相关炎症和心脏代谢疾病的个性化治疗策略。
