Macrophage innate training induced by IL-4 and IL-13 activation enhances OXPHOS driven anti-mycobacterial responses DOI Creative Commons
Mimmi L. E. Lundahl, Morgane Mitermite, Dylan G. Ryan

et al.

eLife, Journal Year: 2022, Volume and Issue: 11

Published: Sept. 29, 2022

Macrophages are a highly adaptive population of innate immune cells. Polarization with IFNγ and LPS into the ‘classically activated’ M1 macrophage enhances pro-inflammatory microbicidal responses, important for eradicating bacteria such as Mycobacterium tuberculosis . By contrast, ‘alternatively M2 macrophages, polarized IL-4, oppose bactericidal mechanisms allow mycobacterial growth. These activation states accompanied by distinct metabolic profiles, where macrophages favor near exclusive use glycolysis, whereas up-regulate oxidative phosphorylation (OXPHOS). Here, we demonstrate that IL-4 IL-13 counterintuitively induces protective memory against challenge. In human murine models, prior IL-4/13 cytokine secretion in response to secondary stimulation ligands. our model, enhanced killing capacity is also demonstrated. Despite this switch phenotype, trained do not M1-typical metabolism, instead retaining heightened OXPHOS. Moreover, inhibition OXPHOS oligomycin, 2-deoxy glucose or BPTES all impeded responses from macrophages. Lastly, work identifies IL-10 attenuates training, impeding mechanisms. summary, provides new unexpected insight alternative context infection.

Language: Английский

Mitochondrial control of inflammation DOI Open Access
Saverio Marchi, Emma Guilbaud, Stephen W. G. Tait

et al.

Nature reviews. Immunology, Journal Year: 2022, Volume and Issue: 23(3), P. 159 - 173

Published: July 25, 2022

Language: Английский

Citations

545
The NLRP3 inflammasome: activation and regulation DOI Creative Commons
Jie Xu, Gabriel Núñez

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 48(4), P. 331 - 344

Published: Nov. 4, 2022

Language: Английский

Citations

275
Mitochondrial dysfunction: mechanisms and advances in therapy DOI Creative Commons

Zong Yao,

Hao Li, Peng Liao

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: May 15, 2024

Abstract Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation disease progression. Particularly, mitochondrial dysfunctions identified many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, cancer. However, the multifaceted nature elusive phenotypic threshold dysfunction complicate our understanding contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among most important therapeutic targets. In recent years, strategies targeting have continuously emerged transitioned clinical trials. Advanced intervention such as using healthy replenish or replace damaged mitochondria, has shown promise preclinical trials various Mitochondrial components, mtDNA, mitochondria-located microRNA, associated proteins can be potential agents augment function immunometabolic diseases tissue injuries. Here, we review current knowledge pathophysiology concrete examples We also summarize treat perspective dietary supplements targeted therapies, well translational situation related pharmacology agents. Finally, this discusses innovations applications transplantation an advanced promising treatment.

Language: Английский

Citations

219
Chronic inflammation and the hallmarks of aging DOI Creative Commons
Jordan J. Baechle, Nan Chen, Priya Makhijani

et al.

Molecular Metabolism, Journal Year: 2023, Volume and Issue: 74, P. 101755 - 101755

Published: June 16, 2023

Recently, the hallmarks of aging were updated to include dysbiosis, disabled macroautophagy, and chronic inflammation. In particular, low-grade inflammation during aging, without overt infection, is defined as "inflammaging," which associated with increased morbidity mortality in population. Emerging evidence suggests a bidirectional cyclical relationship between development age-related conditions, such cardiovascular diseases, neurodegeneration, cancer, frailty. How crosstalk other underlies biological mechanisms disease thus particular interest current geroscience research.

Language: Английский

Citations

153
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production DOI
Alexander Hooftman, Christian G. Peace, Dylan G. Ryan

et al.

Nature, Journal Year: 2023, Volume and Issue: 615(7952), P. 490 - 498

Published: March 8, 2023

Language: Английский

Citations

129
How location and cellular signaling combine to activate the NLRP3 inflammasome DOI Creative Commons

Anil Akbal,

Alesja Dernst,

Marta Lovotti

et al.

Cellular and Molecular Immunology, Journal Year: 2022, Volume and Issue: 19(11), P. 1201 - 1214

Published: Sept. 20, 2022

Abstract NOD-, LRR-, and pyrin domain-containing 3 (NLRP3) is a cytosolic innate immune sensor of cellular stress signals, triggered by infection sterile inflammation. Upon detection an activating stimulus, NLRP3 transitions from inactive homo-oligomeric multimer into active multimeric inflammasome, which promotes the helical oligomeric assembly adaptor molecule ASC. ASC oligomers provide platform for caspase-1 activation, leading to proteolytic cleavage activation proinflammatory cytokines in IL-1 family gasdermin D, can induce lytic form cell death. Recent studies investigating both requirement structure have revealed complex regulation multiple steps involved its activation. This review presents perspective on biochemical processes controlling inflammasome with particular emphasis structural role organelles. We also highlight latest research metabolic control this inflammatory pathway discuss promising clinical targets intervention.

Language: Английский

Citations

126
Innate metabolic responses against viral infections DOI Open Access
Clovis S. Palmer

Nature Metabolism, Journal Year: 2022, Volume and Issue: 4(10), P. 1245 - 1259

Published: Oct. 20, 2022

Language: Английский

Citations

76
Mitochondrial complex I activity in microglia sustains neuroinflammation DOI Creative Commons
Luca Peruzzotti-Jametti,

Carolyn M. Willis,

Grzegorz Krzak

et al.

Nature, Journal Year: 2024, Volume and Issue: 628(8006), P. 195 - 203

Published: March 13, 2024

Abstract Sustained smouldering, or low-grade activation, of myeloid cells is a common hallmark several chronic neurological diseases, including multiple sclerosis 1 . Distinct metabolic and mitochondrial features guide the activation diverse functional states 2 However, how these act to perpetuate inflammation central nervous system unclear. Here, using multiomics approach, we identify molecular signature that sustains microglia through complex I activity driving reverse electron transport production reactive oxygen species. Mechanistically, blocking in pro-inflammatory protects against neurotoxic damage improves outcomes an animal disease model vivo. Complex potential therapeutic target foster neuroprotection inflammatory disorders 3

Language: Английский

Citations

76
DAMPs and DAMP-sensing receptors in inflammation and diseases DOI Open Access
Ming Ma, Wei Jiang, Rongbin Zhou

et al.

Immunity, Journal Year: 2024, Volume and Issue: 57(4), P. 752 - 771

Published: April 1, 2024

Language: Английский

Citations

71
Mitochondrial integrated stress response controls lung epithelial cell fate DOI Creative Commons
SeungHye Han, Minho Lee, Youngjin Shin

et al.

Nature, Journal Year: 2023, Volume and Issue: 620(7975), P. 890 - 897

Published: Aug. 9, 2023

Abstract Alveolar epithelial type 1 (AT1) cells are necessary to transfer oxygen and carbon dioxide between the blood air. 2 (AT2) serve as a partially committed stem cell population, producing AT1 during postnatal alveolar development repair after influenza A SARS-CoV-2 pneumonia 1–6 . Little is known about metabolic regulation of fate lung cells. Here we report that deleting mitochondrial electron transport chain complex I subunit Ndufs2 in mouse gestation led death development. Affected mice displayed hypertrophic with AT2 features, transitional Mammalian I, comprising 45 subunits, regenerates NAD + pumps protons. Conditional expression yeast NADH dehydrogenase (NDI1) protein without proton pumping 7,8 was sufficient correct abnormal avert lethality. Single-cell RNA sequencing revealed enrichment integrated stress response (ISR) genes Administering an ISR inhibitor 9,10 or precursor reduced gene signatures rescued lethality absence function. Notably, epithelial-specific loss II Sdhd , which maintains regeneration, did not trigger high activation These findings highlight unanticipated requirement for I-dependent regeneration directing by preventing pathological induction.

Language: Английский

Citations

62