AlSaeed Halemah, Haider Mohammed J A, Alzaid Fawaz, Al-Mulla Fahd, Ahmad Rasheed, Al-Rashed Fatema
Immunology and Microbiology Department, Dasman Diabetes Institute, Al-Soor Street, Dasman, Kuwait, PO BOX 1180, Dasman 15462, State of Kuwait.
Department of Biological Sciences, Faculty of Science, Kuwait University, PO BOX 5969, Safat 13060, State of Kuwait.
iScience. 2024 May 22;27(7):110046. doi: 10.1016/j.isci.2024.110046. eCollection 2024 Jul 19.
The interplay between lipid metabolism and immune response in macrophages plays a pivotal role in various infectious diseases, notably tuberculosis (TB). Herein, we illuminate the modulatory effect of heat-killed (HKMT) on macrophage lipid metabolism and its implications on the inflammatory cascade. Our findings demonstrate that HKMT potently activates the lipid scavenger receptor, CD36, instigating lipid accumulation. While CD36 inhibition mitigated lipid increase, it unexpectedly exacerbated the inflammatory response. Intriguingly, this paradoxical effect was linked to an upregulation of PPARδ. Functional analyses employing PPARδ modulation revealed its central role in regulating both lipid dynamics and inflammation, suggesting it as a potential therapeutic target. Moreover, primary monocytic cells from diabetic individuals, a demographic at amplified risk of TB, exhibited heightened PPARδ expression and inflammation, further underscoring its pathological relevance. Targeting PPARδ in these cells effectively dampened the inflammatory response, offering a promising therapeutic avenue against TB.
巨噬细胞中脂质代谢与免疫反应之间的相互作用在各种传染病，尤其是结核病（TB）中起着关键作用。在此，我们阐明了热灭活的结核分枝杆菌（HKMT）对巨噬细胞脂质代谢的调节作用及其对炎症级联反应的影响。我们的研究结果表明，HKMT有力地激活脂质清道夫受体CD36，促使脂质积累。虽然抑制CD36可减轻脂质增加，但出乎意料的是，它加剧了炎症反应。有趣的是，这种矛盾的效应与PPARδ的上调有关。采用PPARδ调节的功能分析表明，它在调节脂质动态和炎症方面起着核心作用，表明它是一个潜在的治疗靶点。此外，糖尿病个体（结核病风险增加的人群）的原代单核细胞表现出PPARδ表达和炎症增强，进一步强调了其病理相关性。在这些细胞中靶向PPARδ有效地抑制了炎症反应，为抗结核病提供了一条有前景的治疗途径。
