Microglia are specialized parenchymal‐resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are thought to worsen CNS diseases; nevertheless, their impact during neuroinflammatory processes remains largely obscure. Here, using a combination of single‐cell RNA sequencing and multicolour flow cytometry, we comprehensively profile microglia in the brain of lipopolysaccharide (LPS)‐injected mice. By excluding the contribution of other immune CNS‐resident and peripheral cells, we show that microglia isolated from LPS‐injected mice display a global downregulation of their homeostatic signature together with an upregulation of inflammatory genes. Notably, we identify distinct microglial activated profiles under inflammatory conditions, which greatly differ from neurodegenerative disease‐associated profiles. These results provide insights into microglial heterogeneity and establish a resource for the identification of specific phenotypes in CNS disorders, such as neuroinflammatory and neurodegenerative diseases.

Cancer heterogeneity and progression are subject to complex interactions between neoplastic cells and their microenvironment, including the immune system. Although glioblastomas (GBMs) are classified as ‘cold tumours’ with very little lymphocyte infiltration, they can contain up to 30–40% of tumour-associated macrophages, reported to contribute to a supportive microenvironment that facilitates tumour proliferation, survival and migration. In GBM, tumour-associated macrophages comprise either resident parenchymal microglia, perivascular macrophages or peripheral monocyte-derived cells. They are recruited by GBMs and in turn release growth factors and cytokines that affect the tumour. Notably, tumour-associated microglia/macrophages (TAMs) acquire different expression programs, which shape the tumour microenvironment and contribute to GBM molecular subtyping. Further, emerging evidence highlights that TAM programs may adapt to specific tumour features and landscapes. Here, we review key evidence describing TAM transcriptional and functional heterogeneity in GBM. We propose that unravelling the intricate complexity and diversity of the myeloid compartment as well as understanding how different TAM subsets may affect tumour progression will possibly pave the way to new immune therapeutic avenues for GBM patients.

Although the immunomodulatory and cytoprotective properties of itaconate have been studied extensively, it is not known whether its naturally occurring isomers mesaconate and citraconate have similar properties. Here, we show that itaconate is partially converted to mesaconate intracellularly and that mesaconate accumulation in macrophage activation depends on prior itaconate synthesis. When added to human cells in supraphysiological concentrations, all three isomers reduce lactate levels, whereas itaconate is the strongest succinate dehydrogenase (SDH) inhibitor. In cells infected with influenza A virus (IAV), all three isomers profoundly alter amino acid metabolism, modulate cytokine/chemokine release and reduce interferon signalling, oxidative stress and the release of viral particles. Of the three isomers, citraconate is the strongest electrophile and nuclear factor-erythroid 2-related factor 2 (NRF2) agonist. Only citraconate inhibits catalysis of itaconate by cis-aconitate decarboxylase (ACOD1), probably by competitive binding to the substrate-binding site. These results reveal mesaconate and citraconate as immunomodulatory, anti-oxidative and antiviral compounds, and citraconate as the first naturally occurring ACOD1 inhibitor.