Extracellular Matrix-Induced GM-CSF and Hypoxia Promote Immune Control of in Human Granulomas.

Several cellular models have been developed with the aim to reproduce and dissect human granulomatous responses, the hallmark of tuberculosis (TB) immunopathogenesis. In that context, we compared two- (2D) three-dimensional (3D) granuloma models resulting from infection of human peripheral blood mononuclear cells with () in the absence or presence of a collagen-based extracellular matrix (ECM). Granuloma formation was found to be significantly enhanced in the 2D model. This feature was associated with an earlier chemokine production and lymphocyte activation, but also a significantly increased bacterial burden. Remarkably, the reduction in burden in the 3D model correlated with an increase in GM-CSF production. GM-CSF, which is known to promote macrophage survival, was found to be inherently induced by the ECM. We observed that only 3D granulomas led to the accumulation of lipid inclusions within Our data suggest that a hypoxic environment within the ECM could be responsible for this dormant-like phenotype. Furthermore, exposure to a TNF-α antagonist reverted dormancy, thereby mimicking the reactivation of TB observed in rheumatic patients receiving this therapy. To conclude, we showed that only granulomas generated in the presence of an ECM could recapitulate some clinically relevant features of granulomatous responses in TB. As such, this model constitutes a highly valuable tool to study the interplay between immunity and stress responses as well as to evaluate novel treatment strategies.