Figure 3.

Targeting inflammatory proteins as host-directed therapies (HDTs) for TB to ameliorate tissue inflammation. Arachidonic acid (AA) is metabolized by 5-lipoxygenase (5-LO) to produce leukotriene A4 (LTA₄), a substrate in the subsequent step that is catalyzed by leukotriene A4 hydrolase (LTA4H) to produce the highly inflammatory leukotriene B4 (LTB₄). High levels of LTB₄ drive excessive TNF-α production by macrophages that may trigger necrotic cell death. Necrotic cell death leads to granuloma dissociation resulting in the formation of caseums and eventually cavities after the necrotic center collapses into the airways. Type I IFNs block the production of host protective IL-1α and IL-1β in vitro and in vivo resulting in reduced production of PGE2. Targeting specific inflammatory proteins with chemical inhibitors or antibodies could be a possible HDT aimed at limiting tissue inflammation and improve treatment outcomes. The proof-of-principle for the interventions depicted in the schematic has been established in animal models.