Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically DOI Creative Commons
mingming zhao, Dragana Janković, Verena M. Link

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 25, 2025

Abstract How macrophages in the tissue environment integrate multiple stimuli depends on genetic background of host, but this is still poorly understood. We investigate IL-4 activation male C57BL/6 and BALB/c strain specific vivo tissue-resident (TRMs) from peritoneal cavity. TRMs are more transcriptionally responsive to stimulation, with induced genes associated super enhancers, topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals enrichment NF-κB, IRF, STAT motifs. Additionally, IL-4-activated demonstrate an augmented synergistic response upon vitro lipopolysaccharide (LPS) exposure, despite naïve displaying a robust transcriptional LPS. Single-cell RNA sequencing (scRNA-seq) analysis mixed bone marrow chimeras indicates that differences synergy cell intrinsic within same environment. Hence, variation alters IL-4-induced epigenetic reprogramming resulting responses LPS exposure.

Language: Английский

Rankings of tuberculosis antibiotic treatment regimens are sensitive to spatial scale, detection limit, and initial host bacterial burden DOI Creative Commons
Christian Michael, Maral Budak, Pauline Maiello

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: April 16, 2025

Abstract Pulmonary infection after inhalation of Mycobacterium tuberculosis (Mtb) causes (TB). In humans and non-human primates, TB presents with lung granulomas - complex spheroidal structures composed immune cells bacteria. These often have centralized caseum (necrotic tissue) where mycobacteria are spatially quarantined, complicating antibiotic treatment. It is challenging to untangle which the many host-pathogen interactions drive heterogeneous treatment outcomes observed at between-host within-host scales. Treatment involves administration multiple antibiotics for extended periods time. Determining regimens optimal reducing times toxicity a goal recent eradication campaigns. clinical trials different drug expensive challenging. Here, determine responses various combinations antibiotics, we simulate treatments in HostSim , our whole-host mechanistic, multi-scale computational model Mtb-infection within primates. tracks dynamics pulmonary primate host over molecular, cellular, tissue, organ, We also create heterogenous virtual cohort, comprising distinct hosts, trials. Virtual represented by newly integrated pharmacokinetics / pharmacodynamics drug-interaction model. containing up four commonly-prescribed (e.g., HRZE or BPaL). Our approach allows us identify both (1) hosts/granulomas most improved each treatment, (2) mechanisms influence outcome heterogeneity. recapitulates several known correlate total bacterial burden (CFU) hosts such as volume bactericidal activity T macrophages. By tracking experimental measurements silico virtually recreate rankings from literature. Strikingly, find that ranking methods overall regimen efficacy strongly influenced ‘definition improvement’ used and, some cases, detection threshold CFU. Other depend on initial granulomas. work suggests metrics optimality may be orthogonal, explain seemingly-contradictory findings studies.

Language: Английский

Citations

0
Glycolytic reprogramming in microglia: A potential therapeutic target for ischemic stroke DOI
Guangming Zhang,

Anliu Zhao,

Xiaolu Zhang

et al.

Cellular Signalling, Journal Year: 2024, Volume and Issue: unknown, P. 111466 - 111466

Published: Oct. 1, 2024

Language: Английский

Citations

3
Herbacetin ameliorates lipopolysaccharide-elicited inflammatory response by suppressing NLRP-3/AIM-2 inflammasome activation, PI3K/Akt/MAPKs/NF-κB redox inflammatory signalling, modulating autophagy and macrophage polarization imbalance DOI
Monika Kumari, Anamika Sharma, Narendra Vijay Tirpude

et al.

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: Nov. 16, 2024

Language: Английский

Citations

3
Identification of glutamine as a potential therapeutic target in dry eye disease DOI Creative Commons
Xiaoniao Chen, Chuyue Zhang, Fei Peng

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2025, Volume and Issue: 10(1)

Published: Jan. 21, 2025

Abstract Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded best therapeutic outcome against eye, surpassing monotherapy outcomes. In situ metabolomics matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition reversed anti-inflammatory, anti-apoptotic, homeostasis-preserving effects observed therapy, highlighting critical role Clinical cases rodent model showed elevated expression glutaminase (GLS1), an upstream enzyme metabolism, injury. Mechanistic studies indicated overexpression inhibition GLS1 counteracted enhanced, respectively, anti-inflammatory underscoring GLS1’s pivotal regulating metabolism. Furthermore, single-cell sequencing distinct subset pro-inflammatory pro-fibrotic corneal epithelial model, while treatment downregulated those subclusters, thereby reducing their cytokine secretion. summary, effectively ameliorated occurrence apoptosis by downregulating subclusters related IκBα/NF-κB signaling. The present suggests metabolism plays critical, previously unrecognized DED proposes attractive strategy enhance inhibiting alleviating inflammation-driven progression.

Language: Английский

Citations

0
Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically DOI Creative Commons
mingming zhao, Dragana Janković, Verena M. Link

et al.

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Jan. 25, 2025

Abstract How macrophages in the tissue environment integrate multiple stimuli depends on genetic background of host, but this is still poorly understood. We investigate IL-4 activation male C57BL/6 and BALB/c strain specific vivo tissue-resident (TRMs) from peritoneal cavity. TRMs are more transcriptionally responsive to stimulation, with induced genes associated super enhancers, topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals enrichment NF-κB, IRF, STAT motifs. Additionally, IL-4-activated demonstrate an augmented synergistic response upon vitro lipopolysaccharide (LPS) exposure, despite naïve displaying a robust transcriptional LPS. Single-cell RNA sequencing (scRNA-seq) analysis mixed bone marrow chimeras indicates that differences synergy cell intrinsic within same environment. Hence, variation alters IL-4-induced epigenetic reprogramming resulting responses LPS exposure.

Language: Английский

Citations

0