scholarly journals Cortical microinfarcts potentiate recurrent ischemic injury through NLRP3-dependent trained immunity

2020 ◽  
Author(s):  
Yiwei Feng ◽  
Tengteng Wu ◽  
Yukun Feng ◽  
Fengyin Liang ◽  
Ge Li ◽  
...  
Keyword(s):  
Detrimental Effect ◽  
Recurrent Stroke ◽  
Ischemic Injury ◽  
The Elderly ◽  
Potential Effect ◽  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity ◽  
Photothrombotic Stroke

AbstractMicroinfarcts are common among the elderly, and patients with microinfarcts are more vulnerable to another stroke. However, the potential effect of microinfarct on recurrent stroke remains elusive. In this study, we investigated the detrimental effect of microinfarct on recurrent stroke in mice. Microinfarct was induced using two-photon laser and photothrombotic stroke was induced in the cortex contralateral to microinfarct four weeks later. We found that CMI could trigger the formation of innate immune memory, which exacerbated the pro-inflammatory response and ischemic injury in second photothrombotic stroke. Furthermore, we clarified the role of NLRP3 inflammasome in the nuclei of microglia, which interacts with the MLL1 complex and thereby increases H3K4 methylation, suggesting that NLRP3 is critical in microinfarct-induced innate immune memory. Additionally, NLRP3 knockout in microglia attenuated microinfarct-induced detrimental effects on recurrent stroke. Our study highlights the detrimental effect of trained immunity on the recurrent stroke and reveals the important role of NLRP3 in mediating the formation of this memory, which may be a therapeutic target to mitigate recurrent strokes.

scholarly journals The Role of Cell Metabolism in Innate Immune Memory

2020 ◽  
pp. 1-9
Author(s):  
Anaisa Valido Ferreira ◽  
Jorge Domiguéz-Andrés ◽  
Mihai Gheorghe Netea
Keyword(s):  
Metabolic Pathways ◽  
Tricarboxylic Acid Cycle ◽  
Cell Metabolism ◽  
Innate Immune ◽  
Immune Memory ◽  
Functional Changes ◽  
Trained Immunity ◽  
Health And Disease

Immunological memory is classically attributed to adaptive immune responses, but recent studies have shown that challenged innate immune cells can display long-term functional changes that increase nonspecific responsiveness to subsequent infections. This phenomenon, coined <i>trained immunity</i> or <i>innate immune memory</i>, is based on the epigenetic reprogramming and the rewiring of intracellular metabolic pathways. Here, we review the different metabolic pathways that are modulated in trained immunity. Glycolysis, oxidative phosphorylation, the tricarboxylic acid cycle, amino acid, and lipid metabolism are interplaying pathways that are crucial for the establishment of innate immune memory. Unraveling this metabolic wiring allows for a better understanding of innate immune contribution to health and disease. These insights may open avenues for the development of future therapies that aim to harness or dampen the power of the innate immune response.

scholarly journals The Role of the Pathogen Dose and PI3Kγ in Immunometabolic Reprogramming of Microglia for Innate Immune Memory

2021 ◽  
Vol 22 (5) ◽  
pp. 2578
Author(s):  
Trim Lajqi ◽  
Christian Marx ◽  
Hannes Hudalla ◽  
Fabienne Haas ◽  
Silke Große ◽  
...  
Keyword(s):  
Oxygen Consumption ◽  
Immune Tolerance ◽  
Immune Cells ◽  
Low Dose ◽  
Innate Immune ◽  
Immune Memory ◽  
Innate Immune Cells ◽  
Atp Production ◽  
Dose Dependent

Microglia, the innate immune cells of the CNS, exhibit long-term response changes indicative of innate immune memory (IIM). Our previous studies revealed IIM patterns of microglia with opposing immune phenotypes: trained immunity after a low dose and immune tolerance after a high dose challenge with pathogen-associated molecular patterns (PAMP). Compelling evidence shows that innate immune cells adopt features of IIM via immunometabolic control. However, immunometabolic reprogramming involved in the regulation of IIM in microglia has not been fully addressed. Here, we evaluated the impact of dose-dependent microglial priming with ultra-low (ULP, 1 fg/mL) and high (HP, 100 ng/mL) lipopolysaccharide (LPS) doses on immunometabolic rewiring. Furthermore, we addressed the role of PI3Kγ on immunometabolic control using naïve primary microglia derived from newborn wild-type mice, PI3Kγ-deficient mice and mice carrying a targeted mutation causing loss of lipid kinase activity. We found that ULP-induced IIM triggered an enhancement of oxygen consumption and ATP production. In contrast, HP was followed by suppressed oxygen consumption and glycolytic activity indicative of immune tolerance. PI3Kγ inhibited glycolysis due to modulation of cAMP-dependent pathways. However, no impact of specific PI3Kγ signaling on immunometabolic rewiring due to dose-dependent LPS priming was detected. In conclusion, immunometabolic reprogramming of microglia is involved in IIM in a dose-dependent manner via the glycolytic pathway, oxygen consumption and ATP production: ULP (ultra-low-dose priming) increases it, while HP reduces it.

scholarly journals Trained Immunity and Local Innate Immune Memory in the Lung

Cell ◽  
2018 ◽  
Vol 175 (6) ◽  
pp. 1463-1465 ◽  
Author(s):  
Mihai G. Netea ◽  
Leo A.B. Joosten
Keyword(s):  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity

scholarly journals The Potential Effects of Short-Chain Fatty Acids on the Epigenetic Regulation of Innate Immune Memory

Challenges ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 25
Author(s):  
Raphael Watt ◽  
Kimberley Parkin ◽  
David Martino
Keyword(s):  
Fatty Acids ◽  
Innate Immunity ◽  
Epigenetic Regulation ◽  
Early Life ◽  
Short Chain Fatty Acids ◽  
Innate Immune ◽  
Short Chain ◽  
Immune Memory ◽  
Trained Immunity ◽  
Chain Fatty Acids

The regulation of innate immunity is substantially more ‘plastic’ than previously appreciated. Innate immune memory (manifested through trained immunity and tolerance) is a recently described epigenetic phenomenon that is a model example, with broad implications for infectious disease, allergy and autoimmunity. Training the innate immune system to combat infections and temper inappropriate responses in non-communicable diseases will likely be an area of intense research. Innate immunity is influenced by short chain fatty acids, which are the natural products of digestion by the intestinal microbiota that possess inherent histone deacetylase inhibitory properties. It therefore stands to reason that a healthy gut microbiome may well influence mucosal and systemic trained immunity via short chain fatty acids. There is a lack of data on this specific topic, and we discuss potential relationships based on available and preliminary evidence. Understanding the link between intestinal microbiome composition, capacity for short chain fatty acid production and downstream effects on innate immune memory in early life will have important implications for host immunobiology. In this review we explore the intersection between the gut microbiota, short chain fatty acids and epigenetic regulation of innate immunity with a focus on early life.

scholarly journals Induction of innate immune memory: the role of cellular metabolism

2019 ◽  
Vol 56 ◽  
pp. 10-16 ◽  
Author(s):  
Jorge Domínguez-Andrés ◽  
Leo AB Joosten ◽  
Mihai G Netea
Keyword(s):  
Cellular Metabolism ◽  
Innate Immune ◽  
Immune Memory

scholarly journals Trained immunity: A program of innate immune memory in health and disease

Science ◽  
2016 ◽  
Vol 352 (6284) ◽  
pp. aaf1098-aaf1098 ◽  
Author(s):  
M. G. Netea ◽  
L. A. B. Joosten ◽  
E. Latz ◽  
K. H. G. Mills ◽  
G. Natoli ◽  
...  
Keyword(s):  
Innate Immune ◽  
Immune Memory ◽  
Trained Immunity ◽  
Health And Disease

scholarly journals A Prime Time for Trained Immunity: Innate Immune Memory in Newborns and Infants

Neonatology ◽  
2013 ◽  
Vol 105 (2) ◽  
pp. 136-141 ◽  
Author(s):  
Ofer Levy ◽  
James L. Wynn
Keyword(s):  
Innate Immune ◽  
Immune Memory ◽  
Prime Time ◽  
Trained Immunity

Potential Effect of β-casomorphin-7 on Lymphocyte and TLR\NF-κB Signaling Pathway in Intestinal Mucosa of Aged Mice

2020 ◽  
Author(s):  
Hong Yin ◽  
Xiaqing Su ◽  
Jijie Liu ◽  
Lihua Li ◽  
Lihua Li ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Intestinal Mucosa ◽  
The Elderly ◽  
Potential Effect ◽  
Protective Role ◽  
Control Group ◽  
Relative Expression ◽  
Aged Mice ◽  
Histopathological Studies

The effect of â-Casomorphin-7 on intestinal mucosal immunity was investigated in aged mice. Mice were treated without or with different doses of â-Casomorphin-7 for 30 days. All mice were sacrificed and intestinal mucosa samples collection at the end of the experiment. Histopathological studies showed the tissue protective role of â-Casomorphin-7 in aged mice. The number of duodenal and jejunal epithelial lymphocytes decreased significantly Pandlt;0.05 The doses of duodenal and jejunal epithelial lymphocytes in mice were significantly Pandlt;0.05 increased in each dose group. The relative expression of TLR4,TRAF6 and NF-êB in the intestinal mucosa of the elderly model group was lower than that of the young control group. The low and middle dose groups significantly Pandlt;0.05 up-regulated the relative expression of TLR4, TRAF6 and NF-êB.The results suggest that â-Casomorphin-7 can improved intestinal mucosal immune decline likely through balancing TLR4\NF-êB signaling pathway.

scholarly journals Managing Inflammation after Spinal Cord Injury through Manipulation of Macrophage Function

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Yi Ren ◽  
Wise Young
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Immune Responses ◽  
Potential Effect ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Inflammatory Microenvironment ◽  
Persistent Inflammation ◽  
Cord Injury

Spinal cord injury (SCI) triggers inflammation with activation of innate immune responses that contribute to secondary injury including oligodendrocyte apoptosis, demyelination, axonal degeneration, and neuronal death. Macrophage activation, accumulation, and persistent inflammation occur in SCI. Macrophages are heterogeneous cells with extensive functional plasticity and have the capacity to switch phenotypes by factors present in the inflammatory microenvironment of the injured spinal cord. This review will discuss the role of different polarized macrophages and the potential effect of macrophage-based therapies for SCI.

Sign in / Sign up

Export Citation Format

Share Document