# Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense

## TL;DR

This study uses human stem cell-derived macrophages to show that itaconate plays different roles in defending against tuberculosis in different macrophage types.

## Contribution

The study introduces a human iPSC-derived macrophage model to reveal distinct itaconate functions in macrophage subtypes during M. tuberculosis infection.

## Key findings

- Human macrophages produce less itaconate than mouse macrophages, with alveolar macrophage-like cells producing 4-fold less than MDM-like cells.
- ACOD1-deficient alveolar macrophage-like cells are permissive for Mtb growth, unlike MDM-like cells.
- Itaconate dampens Mtb-induced inflammation in MDM-like cells but not in alveolar macrophage-like cells.

## Abstract

Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

In this study the authors develop a stem cell derived lung alveolar macrophage model and use these cells to dissect the contribution of the inflammation induced metabolite itaconate in defense against M. tuberculosis infection. The findings show that the function of itaconate in host defense differs between human macrophage types.