Abstract: The prognosis for patients who experience intracerebral hemorrhage is poor because of a lack of effective treatments. Tumor necrosis factor-α–stimulated gene 6 (TSG6) is a secreted glycoprotein that exerts anti-inflammatory effects in various inflammatory diseases. We previously showed that adipose-derived stem cells can inhibit inflammation by upregulating TSG6 secretion in an in vitro model of intracerebral hemorrhage. However, the direct effects of TSG6 on hematoma clearance in vivo remain largely unknown. The aim of this study was to determine how TSG6 affects hematoma absorption in mice subjected to intracerebral hemorrhage and to explore the potential underlying mechanisms. We first analyzed the gene profiles of patients with intracerebral hemorrhage from the GEO database and examined changes in TSG6 expression in the brain tissues of mice subjected to intracerebral hemorrhage. We found that TSG6 expression exhibited a transient increase following intracerebral hemorrhage, and that there was a negative correlation between the initial hematoma volume and TSG6 levels. Immunofluorescence analysis showed that TSG6 was primarily expressed in microglia and macrophages. Furthermore, we found that TSG6 promoted functional recovery in mice subjected to intracerebral hemorrhage by accelerating hematoma clearance, reducing the number of apoptotic cells and degenerated neurons, increasing the proportion of phagocytic microglia/macrophages, and decreasing iron deposition. Western blotting and immunofluorescence analysis indicated that TSG6 promoted M2 polarization of microglia/macrophages. In vitro phagocytosis experiments confirmed that TSG6 enhanced the ability of microglia to phagocytize red blood cells. Finally, we identified the signal transducer and activator of transcription 6/growth arrest–specific protein 6 signaling pathway as playing a critical role in TSG6-mediated hematoma absorption. In summary, our results demonstrate an essential role for TSG6 in promoting hematoma absorption in a mouse model of intracerebral hemorrhage. These findings suggest that TSG6 accelerates hematoma clearance and improves neurological function by promoting microglia/macrophage polarization to the M2 phenotype, activating the STAT6/GAS6 signaling pathway, and increasing phagocytic receptor expression on the surface of phagocytes, thereby enhancing their ability to phagocytize red blood cells.

Key words: apoptosis, growth arrest–specific protein 6, hematoma absorption, inflammation, intracerebral hemorrhage, iron deposition, microglia/macrophages, polarization, signal transducer and activator of transcription 6, tumor necrosis factor-α–stimulated gene 6