Galectin-3 Mediates Heme-Induced Multi-Organ Dysfunction by Modulating the Splenic Immune Microenvironment

Acute intravascular hemolysis is associated with the release of labile heme, which contributes to systemic inflammation and organ dysfunction. Galectin-3 (Gal-3) is a known modulator of inflammatory responses. However, its specific role in heme-induced organ injury remains to be fully elucidated.

We used a phenylhydrazine (PHZ)-induced model of acute hemolysis in wild-type (WT) and Gal-3 knockout (KO) mice to investigate the influence of Gal-3 on tissue alterations and the inflammatory response.

Despite equivalent levels of hemolysis and anemia in both genotypes, Gal-3 deficiency was associated with reduced injury in the liver, kidneys, and pancreas. In WT mice, Gal-3 was associated with a pro-inflammatory splenic microenvironment. Conversely, Gal-3 KO mice exhibited a shift toward an immunoregulatory phenotype, characterized by an increased frequency of CD4 + CD25 + FoxP3+ regulatory T cells and IL-10+ macrophages. This shift correlated with preserved organ architecture and a more controlled inflammatory profile.

Our findings suggest that Gal-3 may act as a mediator of heme-induced systemic inflammation. By influencing the splenic immune microenvironment and promoting a regulatory phenotype, the absence of Gal-3 appears to alleviate multi-organ stress, suggesting its potential as a target for modulating complications during acute hemolytic crises.