GO‐PEG Represses the Progression of Liver Inflammation via Regulating the M1/M2 Polarization of Kupffer Cells

• Published in: Small (Weinheim an der Bergstrasse, Germany) Vol. 20; no. 26; pp. e2306483 - n/a
• Main Authors: Ding, Xiaomeng, Pang, Yanting, Liu, Qing, Zhang, Haopeng, Wu, Jiawei, Lei, Jialin, Zhang, Ting
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 01.06.2024
• Subjects: Animals; Apoptosis - drug effects; Biological effects; cell crosstalk; Cell Line; Cell Polarity - drug effects; Disease Progression; Graphene; Graphite - chemistry; Graphite - pharmacology; Immune system; Inflammation; Inflammation - metabolism; Inflammation - pathology; KCs; Kupffer Cells - drug effects; Kupffer Cells - metabolism; Lipopolysaccharides - pharmacology; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; liver inflammation; macrophage polarization; Male; Mice; Mice, Inbred C57BL; Nanomaterials; Oxidative Stress - drug effects; Polarization; Polyethylene glycol; Polyethylene Glycols - chemistry; Polyethylene Glycols - pharmacology; polyethylene glycol‐modified graphene oxide (GO‐PEG); Receptors; macrophage polarization; KCs; liver inflammation; cell crosstalk; polyethylene glycol‐modified graphene oxide (GO‐PEG)
• ISSN: 1613-6810; 1613-6829; 1613-6829
• DOI: 10.1002/smll.202306483

As a highly promising nanomaterial, exploring the impact of the liver, a vital organ, stands out as a crucial focus in the examination of its biological effects. Kupffer cells (KCs) are one of the first immune cells to contact with exotic‐substances in liver. Therefore, this study investigates the immunomodulatory effects and mechanisms of polyethylene glycol‐modified graphene oxide (GO‐PEG) on KCs. Initial RNA‐seq and KEGG pathway analyses reveal the inhibition of the TOLL‐like receptor, TNF‐α and NOD‐like receptor pathways in continually stimulated KCs exposed to GO‐PEG. Subsequent biological experiments validate that a 48‐hour exposure to GO‐PEG alleviates LPS‐induced KCs immune activation, characterized by a shift in polarization from M1 to M2. The underlying mechanism involves the absorption of double‐stranded RNA/single‐stranded RNA, inhibiting the activation of TLR3 and TLR7 in KCs. Employing a Kupffer/AML12 cell co‐culture model and animal studies, it is observed that GO‐PEG indirectly inhibit oxidative stress, mitochondrial dysfunction, and apoptosis in AML12 cells, partially mitigating systemic inflammation and preserving liver tissue/function. This effect is attributed to the paracrine interaction between KCs and hepatocytes. These findings suggest a meaningful and effective strategy for treating liver inflammation, particularly when combined with anti‐inflammatory drugs. At both cellular and animal levels, Polyethylene glycol‐modified graphene oxide accumulated in endosomes interferes with TLR3/7 activation by adsorbing ds/ssRNA, thereby regulating the immune response of liver macrophages and promoting alternative activation (M2). The corresponding inflammatory mediators further alleviate the progression of liver inflammation through the crosstalk between liver macrophages and hepatocytes.