NLRP3/Caspase-1/GSDMD pyroptosis pathway drives intestinal barrier dysfunction in asymptomatic HIV infection

Intestinal barrier dysfunction is a recognized early pathological feature in HIV infection, contributing to chronic inflammation and disease progression through microbial translocation. Despite its critical role, the precise molecular mechanisms driving this dysfunction in asymptomatic individuals remain incompletely understood. Current understanding points to immune activation and inflammation, but specific pathways like pyroptosis, a highly inflammatory form of programmed cell death, have not been fully elucidated in this context. Identifying these mechanisms is crucial for developing targeted therapies to preserve gut integrity and mitigate systemic inflammation in people living with HIV (PLWH).

This cross-sectional observational study investigated the NLRP3/Caspase-1/GSDMD pyroptosis pathway in 20 asymptomatic people living with HIV (PLWH) and 15 matched healthy controls. Researchers collected mucosal biopsies and blood samples from all participants. Key markers assessed included the expression of NLRP3, Caspase-1, and GSDMD-NT (N-terminal fragment of Gasdermin D), along with tight junction proteins Occludin and ZO-1. Additionally, levels of inflammatory cytokines IL-1β and IL-18, and bacterial endotoxin LPS were measured. Correlations between these markers and CD4+ T-cell counts were also analyzed.

The study revealed significant mucosal abnormalities in PLWH compared to controls, characterized by distinct molecular changes. Researchers observed upregulated expression of NLRP3, Caspase-1, and GSDMD-NT in the intestinal mucosa of PLWH, indicating activation of the pyroptosis pathway. Concurrently, levels of crucial tight junction proteins, Occludin and ZO-1, were reduced, suggesting compromised intestinal barrier integrity. Furthermore, inflammatory markers IL-1β, IL-18, and LPS were elevated in PLWH.

NLRP3 activation correlated negatively with Occludin and ZO-1 expression, and positively with LPS levels, strongly linking inflammasome activity to barrier disruption and microbial translocation. Intriguingly, CD4+ T-cell counts showed a negative correlation with inflammasome activation, implying that immune compromise may exacerbate pyroptotic processes. These findings collectively establish a clear association between NLRP3-mediated pyroptosis and intestinal barrier disruption in asymptomatic HIV infection.