STAT3 blockade ameliorates LPS-induced kidney injury through macrophage-driven inflammation

作者：Song Hee Lee, Kyu Hong Kim, Seong Min Lee, Seongjoon Park, Sunhwa Lee, Ran‐hui Cha, Jae Wook Lee, Dong Ki Kim, Yon Su Kim, Sang‐Kyu Ye, Seung Hee Yang · 发表于：Cell Communication and Signaling · 年份：2024 · DOI：10.1186/s12964-024-01841-1 · 被引用次数：72 · 研究领域：Acute Kidney Injury Research、Cytokine Signaling Pathways and Interactions、Chronic Kidney Disease and Diabetes

Abstract Background Signal transducer and activator of transcription 3 (STAT3), a multifaceted transcription factor, modulates host immune responses by activating cellular response to signaling ligands. STAT3 has a pivotal role in the pathophysiology of kidney injury by counterbalancing resident macrophage phenotypes under inflammation conditions. However, STAT3’s role in acute kidney injury (AKI), particularly in macrophage migration, and in chronic kidney disease (CKD) through fibrosis development, remains unclear. Methods Stattic (a JAK2/STAT3 inhibitor, 5 mg/kg or 10 mg/kg) was administered to evaluate the therapeutic effect on LPS-induced AKI (L-AKI) and LPS-induced CKD (L-CKD), with animals sacrificed 6–24 h and 14 days post-LPS induction, respectively. The immune mechanisms of STAT3 blockade were determined by comparing the macrophage phenotypes and correlated with renal function parameters. Also, the transcriptomic analysis was used to confirm the anti-inflammatory effect of L-AKI, and the anti-fibrotic role was further evaluated in the L-CKD model. Results In the L-AKI model, sequential increases in BUN and blood creatinine levels were time-dependent, with a marked elevation of 0–6 h after LPS injection. Notably, two newly identified macrophage subpopulations (CD11b high F4/80 low and CD11b low F4/80 high ), exhibited population changes, with an increase in the CD11b high F4/80 low population and a decrease in the CD11b low F4/80 high macrophages. Corresponding to th...