bims-traimu 2025-04-27 papers

bims-traimu

Biomed News

on Trained immunity

Issue of 2025–04–27
six papers selected by
Yantong Wan, Southern Medical University

Cellular and Molecular Mechanisms of Innate Memory Responses.
Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.
Microglia endotoxin tolerance is retained after enforced repopulation.
A host-pathogen metabolic synchrony that facilitates disease tolerance.
Bidirectional Communication Between the Innate and Adaptive Immune Systems.
Cold memories control whole-body thermoregulatory responses.

Annu Rev Immunol. 2025 Apr;43(1): 615-640

Cellular and Molecular Mechanisms of Innate Memory Responses.

Musa M Mhlanga, Stephanie Fanucchi, Mumin Ozturk, Maziar Divangahi.

  There has been an increasing effort to understand the memory responses of a complex interplay among innate, adaptive, and structural cells in peripheral organs and bone marrow. Trained immunity is coined as the de facto memory of innate immune cells and their progenitors. These cells acquire epigenetic modifications and shift their metabolism to equip an imprinted signature to a persistent fast-responsive functional state. Recent studies highlight the contribution of noncoding RNAs and modulation of chromatin structures in establishing this epigenetic readiness for potential immune perturbations. In this review, we discuss recent studies that highlight trained immunity-mediated memory responses emerging intrinsically in innate immune cells and as a complex interplay with other cells at the organ level. Lastly, we survey epigenetic contributors to trained immunity phenotypes-specifically, a recently discovered regulatory circuit coordinating the regulation of a key driver of trained immunity.

Keywords:  epigenetics; immunometabolism; innate immunity; noncoding RNA; organ-trained immunity; vaccine immunology

DOI:  https://doi.org/10.1146/annurev-immunol-101721-035114
Cell Rep. 2025 Apr 22. pii: S2211-1247(25)00372-9. [Epub ahead of print]44(5): 115601

Shigella-trained pro-inflammatory macrophages protect zebrafish from secondary infection.

Margarida C Gomes, Dominik Brokatzky, Serge Mostowy.

  Shigella is an important human pathogen that has no licensed vaccine. Despite decades of seminal work suggesting that its pathogenicity relies on inflammatory cell death of macrophages, the in vivo role of macrophages in controlling Shigella infection remains poorly understood. Here, we use a zebrafish model of innate immune training to investigate the antibacterial role of macrophages following a non-lethal Shigella infection. We found that macrophages are crucial for zebrafish larvae survival during secondary Shigella infection. Consistent with signatures of trained immunity, we demonstrate that bacteria are cleared during training and that protection is independent of the secondary infection site. We show that following Shigella training, macrophages have altered mono- and tri-methylation on lysine 4 in histone 3 (H3K4me1/me3) deposition and shift toward a pro-inflammatory state, characterized by increased tumor necrosis factor alpha (TNF-α) expression and antibacterial reactive oxygen species (ROS) production. We conclude that macrophages are epigenetically reprogrammed by Shigella infection to enhance pro-inflammatory and protective responses.

Keywords:  CP: Immunology; CP: Microbiology; Shigella; infection biology; macrophages; trained immunity; zebrafish

DOI:  https://doi.org/10.1016/j.celrep.2025.115601
Brain Behav Immun. 2025 Apr 22. pii: S0889-1591(25)00144-8. [Epub ahead of print]

Microglia endotoxin tolerance is retained after enforced repopulation.

Tiago Medeiros-Furquim, Anneke Miedema, Edwin Schilder, Nieske Brouwer, Inge R Holtman, Susanne M Kooistra, Bart J L Eggen.

  Microglia are crucial for CNS homeostasis and are involved in a wide range of neurodegenerative and neuroinflammatory diseases. Systemic inflammation and infections can contribute to neurodegeneration later in life by affecting microglia. Like other innate immune cells, microglia can develop innate immune memory (IMM) in response to an inflammatory challenge, altering their response to subsequent stimuli. IMM can ameliorate or worsen CNS pathology, but it is unclear if IMM can be reversed to restore microglia functions. Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced endotoxin tolerance in mice. Repopulated microglia displayed a reduced expression of homeostatic genes and genes related to mitochondrial respiration and TCA cycle metabolism and an increased expression of immune effector and activation genes. Nonetheless the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications.

Keywords:  BLZ945; CSF1R; CSF1R-inhibitor; Depletion; Endotoxin tolerance; Innate immune memory; Microglia; Neuroinflammation; Repopulation; Sotuletinib

DOI:  https://doi.org/10.1016/j.bbi.2025.04.014
Nat Commun. 2025 Apr 19. 16(1): 3729

A host-pathogen metabolic synchrony that facilitates disease tolerance.

Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.

Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.

DOI: https://doi.org/10.1038/s41467-025-59134-1
Annu Rev Immunol. 2025 Apr;43(1): 489-514

Bidirectional Communication Between the Innate and Adaptive Immune Systems.

Kathrynne A Warrick, Charles N Vallez, Hannah E Meibers, Chandrashekhar Pasare.

  Effective bidirectional communication between the innate and adaptive immune systems is crucial for tissue homeostasis and protective immunity against infections. The innate immune system is responsible for the early sensing of and initial response to threats, including microbial ligands, toxins, and tissue damage. Pathogen-related information, detected primarily by the innate immune system via dendritic cells, is relayed to adaptive immune cells, leading to the priming and differentiation of naive T cells into effector and memory lineages. Memory T cells that persist long after pathogen clearance are integral for durable protective immunity. In addition to rapidly responding to reinfections, memory T cells also directly instruct the interacting myeloid cells to induce innate inflammation, which resembles microbial inflammation. As such, memory T cells act as newly emerging activators of the innate immune system and function independently of direct microbial recognition. While T cell-mediated activation of the innate immune system likely evolved as a protective mechanism to combat reinfections by virulent pathogens, the detrimental outcomes of this mechanism manifest in the forms of autoimmunity and other T cell-driven pathologies. Here, we review the complexities and layers of regulation at the interface between the innate and adaptive immune systems to highlight the implications of adaptive instruction of innate immunity in health and disease.

Keywords:  CAR-T cells; T cell memory; TNF superfamily; autoimmunity; cytokine storms; microbial defense; sterile inflammation

DOI:  https://doi.org/10.1146/annurev-immunol-083122-040624
Nature. 2025 Apr 23.

Cold memories control whole-body thermoregulatory responses.

Andrea Muñoz Zamora, Aaron Douglas, Paul B Conway, Esteban Urrieta, Taylor Moniz, James D O'Leary, Lydia Marks, Christine A Denny, Clara Ortega-de San Luis, Lydia Lynch, Tomás J Ryan.

Environmental thermal challenges trigger the brain to coordinate both autonomic and behavioural responses to maintain optimal body temperature1-4. It is unknown how temperature information is precisely stored and retrieved in the brain and how it is converted into a physiological response. Here we investigated whether memories could control whole-body metabolism by training mice to remember a thermal challenge. Mice were conditioned to associate a context with a specific temperature by combining thermoregulatory Pavlovian conditioning with engram-labelling technology, optogenetics and chemogenetics. We report that if mice are returned to an environment in which they previously experienced a 4 °C cold challenge, they increase their metabolic rates regardless of the actual environmental temperature. Furthermore, we show that mice have increased hypothalamic activity when they are exposed to the cold, and that a specific network emerges between the hippocampus and the hypothalamus during the recall of a cold memory. Both natural retrieval and artificial reactivation of cold-sensitive memory engrams in the hippocampus mimic the physiological responses that are seen during a cold challenge. These ensembles are necessary for cold-memory retrieval. These findings show that retrieval of a cold memory causes whole-body autonomic and behavioural responses that enable mice to maintain thermal homeostasis.

DOI: https://doi.org/10.1038/s41586-025-08902-6