Itaconate's differing roles in human macrophages against tuberculosis

Tuberculosis remains a major global health threat, and macrophages—immune cells that live in the lung and elsewhere—are the first line of defense against the bacterium Mycobacterium tuberculosis (Mtb). Laboratory studies in mice have shown that the metabolite itaconate, produced by the enzyme encoded by ACOD1, can shape how macrophages respond to infection. But whether human macrophages make and use itaconate the same way, and whether different human macrophage subtypes behave differently, was not clear. Michael S. Glickman and collaborators set out to clarify this using human induced pluripotent stem cell (hiPSC) technology. They generated two kinds of human macrophages from hiPSCs: cells treated with GM-CSF to resemble alveolar macrophages (AM-Like cells) and cells treated with M-CSF as a control population (MCDM cells). This strategy allowed the team to compare macrophage subtypes in a genetically tractable human model and to test how itaconate and ACOD1 influence macrophage responses to Mtb in a controlled laboratory setting.

The researchers compared itaconate levels and responses to Mtb across their human macrophage models and to mouse macrophages. They found that both human macrophage types produced substantially less itaconate than mouse macrophages, with AM-Ls producing about four-fold less itaconate than MCDMs. To test the role of ACOD1 and itaconate more directly, they examined ACOD1 deficient AM-L macrophages and MCDM macrophages. Strikingly, ACOD1 deficient AM-L macrophages were permissive for Mtb growth—meaning the bacteria grew in those cells—whereas ACOD1 deficiency did not make MCDM macrophages permissive. The team also observed that itaconate suppressed the Mtb-induced inflammatory response in MCDMs but not in AM-L macrophages, with effects on both the Type I IFN and TNF pathways. These results emerged using the exact tools and markers named in the study: hiPSC-derived macrophages, GM-CSF, M-CSF, ACOD1, itaconate, AM-Like cells, MCDM cells, and Mtb.

The findings show that itaconate plays distinct, subtype-specific roles in human macrophages during Mtb infection. In lung-like AM-Like macrophages, lower itaconate production and ACOD1 loss allowed Mtb to grow, suggesting these cells rely on ACOD1-mediated defenses. By contrast, in MCDM macrophages itaconate acted mainly to tone down inflammation—reducing activity in Type I IFN and TNF pathways—without the same effect on bacterial control. The difference between human and mouse macrophages in itaconate production also highlights a key species gap that could affect how therapies translate from animal models to people. Practically, the work validates hiPSC-derived macrophages as a flexible human model for dissecting host-pathogen interactions and for testing genetic or metabolic interventions that might one day refine TB treatments by targeting specific macrophage subtypes or their metabolic pathways.