Innovative Insights into Interleukin-Mediated Macrophage Polarization: Metabolic Reprogramming and Inflammatory...

To clarify the molecular mechanisms of interleukin-macrophage polarization axis in reshaping renal inflammatory microenvironment and driving chronic kidney disease (CKD) progression, and explore targeted therapeutic potential.

We systematically searched the PubMed and Embase databases for published studies from January 2015 to March 2026. The search terms used were "chronic kidney disease" or "CKD", "interleukin" or "IL" or "leukocyte protein network", "macrophages" and "inflammation". A total of 186 peer-reviewed studies based on human and animal models were included, with all non-eligible articles excluded in the screening process.

Pro-inflammatory interleukins (IL-1β/IL-6/IL-17) orchestrate M1 polarization via multi-pathway crosstalk: IL-1β activates NLRP3 inflammasome to promote IL-18 release, IL-6 binds gp130 to trigger STAT3, and IL-17 activates NF-κB/MAPK, all upregulating glycolytic enzymes (HK2/PFKFB3) and M1 markers (iNOS/CD86). Activated M1 macrophages secrete TNF-α/IL-1β/IL-6, forming an autocrine loop to amplify renal parenchymal injury and monocyte recruitment. Anti-inflammatory interleukins (IL-10/IL-22) induce protective M2 polarization: IL-4 activates STAT6 to upregulate CD206/Arg1, IL-10 inhibits NF-κB, and IL-22 modulates AMPK-mediated mitophagy. However, CKD-induced M2 pathological deviation (elevated TGF-β/CTGF, reduced IL-10) converts reparative functions to profibrotic effects, accelerating glomerulosclerosis. This polarization imbalance forms a vicious cycle with interleukin dysregulation. Targeted interventions show efficacy: tocilizumab (anti-IL-6R) reduces M1 infiltration and urinary albumin; paeoniflorin upregulates IL-10 via KLF4 to induce M2; SGLT2 inhibitors enhance IL-22/AMPK signaling; astragaloside IV promotes IL-4/PPARγ to stabilize M2 polarization, all alleviating inflammation and fibrosis.

The interleukin-macrophage polarization axis, regulated by inflammatory pathways and metabolic reprogramming, is a core CKD therapeutic target, supporting multi-target precision interventions.