bims-ainimu 2025-11-16 papers

Issue of 2025–11–16
two papers selected by
Pedro Escoll Guerrero, Institut Pasteur

Immunohorizons. 2025 Nov 09. pii: vlaf051. [Epub ahead of print]9(11):

Shared and distinct responses of human and murine alveolar macrophages and monocyte-derived macrophages to Mycobacterium tuberculosis.

Kimberly A Dill-McFarland, Glenna Peterson, Pamelia N Lim, Shawn Skerrett, Thomas R Hawn, Alissa C Rothchild, Monica Campo.

Macrophages are important sites of bacterial replication and host immune responses during Mycobacterium tuberculosis (Mtb) infection with distinct roles for alveolar macrophages (AMs) early in infection and monocyte-derived macrophages (MDMs) later in disease. Here, we leverage data from human and mouse models to perform a cross-species analysis of macrophage responses to Mtb. Overall, we find that both subsets of human and murine macrophages mount a strong interferon response to Mtb infection. However, AMs across both species do not generate as strong a pro-inflammatory response as human MDMs or murine bone marrow-derived macrophages (BMDMs), as characterized by TNFA signaling and inflammatory response pathways. Interestingly, AMs from mice that were previously vaccinated with BCG (scBCG) or from a model of contained TB (coMtb) had more similar responses to human AMs than control mice. We also identify species-specific pathways altered by infection differently in mouse and human macrophages, including cholesterol homeostasis. Lastly, to investigate downstream effects of the macrophage interferon responses, we examine expression of interleukin (IL)-10, an immunosuppressive cytokine induced by Type I Interferons, and c-Maf, a transcription factor required for myeloid IL-10 expression. We find that c-Maf and IL-10 have significantly lower expression in AMs compared to MDMs in both humans and mice, suggesting one possible mechanism by which AMs mount a stronger interferon response following Mtb infection. Overall, these results highlight the dynamics of innate myeloid responses throughout Mtb infection and the benefit of a combined analysis across species to reveal conserved and unique responses.

Keywords: Mycobacterium tuberculosis ; alveolar macrophages; innate response; interferons; monocyte-derived macrophages

DOI: https://doi.org/10.1093/immhor/vlaf051

Nat Commun. 2025 Nov 13. 16(1): 9992

A Pseudomonas aeruginosa quorum-sensing metabolite manipulates macrophage ferroptosis through a methylation pathway.

Tianyuan Jia, Fengming Li, Tianzhen Li, Anmin Ren, Peiyi Lu, Yiling Liu, Yachun Zhou, Xiangke Duan, Yang Liu, Lin Zhong, Zhirong Zhang, Chris Soon Heng Tan, Liang Yang.

Ferroptosis is a type of iron- and lipid peroxidation-dependent programmed cell death that is involved in various diseases. Some pathogens manipulate host ferroptosis for pathogenesis; however, the potential mechanisms of action remain unclear. Pseudomonas aeruginosa is an opportunistic pathogen that relies on iron for its virulence, biofilm formation, and survival. Here, we report that P. aeruginosa employs the quorum-sensing metabolite, Pseudomonas quinolone signal (PQS), to induce ferroptosis in macrophages through a carnosine-N-methyltransferase (CNMT)-transferrin receptor 1 (TFR1) methylation pathway. Specifically, PQS promotes iron-dependent lipid peroxidation to induce ferroptosis in macrophages. Using high-resolution mass spectrometry-based cellular thermal shift assay (MS-CETSA)/thermal proteome profiling, we identify CNMT as the direct intracellular receptor of PQS in macrophages. Mechanistically, PQS binding increases the histidine methyltransferase (His MTase) activity of CNMT, catalysing methylation of TFR1 at His35. This methylation increases TFR1 protein production, resulting in amplified iron acquisition for ferroptosis. Crucially, the PQS-CNMT-TFR1 axis is distinct from canonical bacterial pathogens that exploit host cell death pathways, revealing the unique strategy of P. aeruginosa to exploit host epigenetic machinery.

DOI: https://doi.org/10.1038/s41467-025-65142-y