Galectin-9 mediates gut-associated inflammation and disruption of tight junctions

Abstract

Abstract Background: High levels of Galectin-9 (Gal-9), a β-galactoside-binding mammalian lectin, are associated with systemic inflammation in chronic viral infections like HIV, despite viral suppression by ART. Gut-systemic microbial translocation is a major contributor of persistent inflammation. Whether Gal-9 influences the integrity of the gut during viral infections remains unknown. Objective: Here we investigated the impact of Gal-9 in the interplay between gut-systemic microbial translocation in the setting of well-treated chronic HIV infection. Method: We assessed the levels of Gal-9 and sCD14 in the plasma of people with HIV on ART (PWH; n=25) and people without HIV (PWOH; n=15) by ELISA. The integrity of the gut epithelium in the presence and absence of rGal-9 was assessed in the HT-29 cell line by immunofluorescence. TNFa was used as a positive control to disrupt gut integrity. The levels of TNFa were measured by qPCR. Non parametric tests were used in the analysis. Results: Plasma Gal-9 and sCD14 were elevated in PWH compared to PWOH (all p<0.0001). Further, high Gal-9 levels correlated with high sCD14 in both the PWH (r=0.43, p=0.0317) and PWOH (r=0.79, p=0.0006) groups. Immunofluorescence revealed disruption of the Claudin tight junctions in vitroafter 24 hrs of rGal-9 treatment. rGal-9 also induced a 6-fold increase in the expression of TNFα in HT-29 cells. Conclusion: Our results show that Gal-9 is associated with markers of gut-systemic microbial translocation irrespective of HIV status and given the direct effects of rGal-9 on tight junction barrier function, targeting Gal-9 either by exploiting its secretory pathways or competitive blockade may serve as a novel therapeutic approach to control gut-associated inflammation.