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 Dysfunction in Neurodegenerative Diseases: Mechanisms and Corresponding Therapeutic Strategies DOI Creative Commons
Kai Meng, Hongyun Jia,

Xiaoqing Hou

et al.

Biomedicines, Journal Year: 2025, Volume and Issue: 13(2), P. 327 - 327

Published: Jan. 31, 2025

Neurodegenerative disease (ND) refers to the progressive loss and morphological abnormalities of neurons in central nervous system (CNS) or peripheral (PNS). Examples neurodegenerative diseases include Alzheimer's (AD), Parkinson's (PD), amyotrophic lateral sclerosis (ALS). Recent studies have shown that mitochondria play a broad role cell signaling, immune response, metabolic regulation. For example, mitochondrial dysfunction is closely associated with onset progression variety diseases, including ND, cardiovascular diabetes, cancer. The energy metabolism, imbalance dynamics, abnormal mitophagy can lead homeostasis, which induce pathological reactions such as oxidative stress, apoptosis, inflammation, damage system, participate occurrence development degenerative AD, PD, ALS. In this paper, latest research progress subject detailed. mechanisms mitophagy-mediated ND are reviewed from perspectives β-amyloid (Aβ) accumulation, dopamine neuron damage, superoxide dismutase 1 (SOD1) mutation. Based on mechanism research, new ideas methods for treatment prevention proposed.

Language: Английский

Citations

2
Neuroinflammation and immunometabolism in neurodegenerative diseases DOI

Neha Lonkar,

Eicke Latz, Róisín M. McManus

et al.

Current Opinion in Neurology, Journal Year: 2025, Volume and Issue: 38(2), P. 163 - 171

Published: Feb. 12, 2025

Immunometabolism is an emerging field of research investigating the ability immune cells to modulate their metabolic activity for optimal function. While this has been extensively examined in peripheral like macrophages, only recently have these studies extended assess immunometabolic microglia, innate brain. Microglia are highly metabolically flexible and can utilize different nutrients diverse functions. Like other cells, they undergo reprogramming on stimulation inflammatory, neurodegenerative conditions such as Alzheimer's disease (AD). In recent years, researchers looked at intricate mechanisms that microglial uncovered key links between altered metabolism, neuroinflammation, involvement disease-associated risk genes. This review highlights significantly contributed our understanding dysregulation observed activated microglia AD, unveiling novel targets therapeutic intervention.

Language: Английский

Citations

2
Pro-inflammatory macrophages produce mitochondria-derived superoxide by reverse electron transport at complex I that regulates IL-1β release during NLRP3 inflammasome activation DOI Creative Commons
Alva M. Casey, Dylan G. Ryan, Hiran A. Prag

et al.

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

Abstract Macrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show LPS-stimulated bone-marrow-derived macrophages produce reverse electron transport (RET) at complex I chain. Using chemical biology genetic approaches, demonstrate production driven metabolic reprogramming, which increases proton motive force (∆p), primarily elevated membrane potential (Δψ m ) maintains a reduced CoQ pool. The key changes are repurposing ATP from oxidative phosphorylation to glycolysis, reduces reliance on F 1 O -ATP synthase activity resulting in higher ∆p, while oxidation succinate sustains Furthermore, mtROS RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, ROS generated an important signal macrophage cytokine production.

Language: Английский

Citations

2
NLRP3 inflammasome in neurodegenerative disease DOI
Faith L. Anderson,

Karl Biggs,

Brynn E. Rankin

et al.

Translational research, Journal Year: 2022, Volume and Issue: 252, P. 21 - 33

Published: Aug. 9, 2022

Language: Английский

Citations

67
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

Citations

54