bims-traimu 2022-06-12 papers

Issue of 2022‒06‒12
five papers selected by
Yantong Wan
Southern Medical University

Annu Rev Virol. 2022 Jun 08.

Shifting the Immune Memory Paradigm: Trained Immunity in Viral Infections.

Esther J M Taks, Simone J C F M Moorlag, Mihai G Netea, Jos W M van der Meer.

Trained immunity is defined as the de facto memory characteristics induced in innate immune cells after exposure to microbial stimuli after infections or certain types of vaccines. Through epigenetic and metabolic reprogramming of innate immune cells after exposure to these stimuli, trained immunity induces an enhanced nonspecific protection by improving the inflammatory response upon restimulation with the same or different pathogens. Recent studies have increasingly shown that trained immunity can, on the one hand, be induced by exposure to viruses; on the other hand, when induced, it can also provide protection against heterologous viral infections. In this review we explore current knowledge on trained immunity and its relevance for viral infections, as well as its possible future uses. Expected final online publication date for the Annual Review of Virology, Volume 9 is September 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-virology-091919-072546

Int J Mol Sci. 2022 May 31. pii: 6166. [Epub ahead of print]23(11):

LXRα Regulates oxLDL-Induced Trained Immunity in Macrophages.

Hannes M Findeisen, Vivienne C Voges, Laura C Braun, Jannik Sonnenberg, Dennis Schwarz, Helena Körner, Holger Reinecke, Yahya Sohrabi.

Reprogramming of metabolic pathways in monocytes and macrophages can induce a proatherosclerotic inflammatory memory called trained innate immunity. Here, we have analyzed the role of the Liver X receptor (LXR), a crucial regulator of metabolism and inflammation, in oxidized low-density lipoprotein (oxLDL)-induced trained innate immunity. Human monocytes were incubated with LXR agonists, antagonists, and oxLDL for 24 h. After five days of resting time, cells were restimulated with the TLR-2 agonist Pam3cys. OxLDL priming induced the expression of LXRα but not LXRβ. Pharmacologic LXR activation was enhanced, while LXR inhibition prevented the oxLDL-induced inflammatory response. Furthermore, LXR inhibition blocked the metabolic changes necessary for epigenetic reprogramming associated with trained immunity. In fact, enrichment of activating histone marks at the IL-6 and TNFα promotor was reduced following LXR inhibition. Based on the differential expression of the LXR isoforms, we inhibited LXRα and LXRβ genes using siRNA in THP1 cells. As expected, siRNA-mediated knock-down of LXRα blocked the oxLDL-induced inflammatory response, while knock-down of LXRβ had no effect. We demonstrate a specific and novel role of the LXRα isoform in the regulation of oxLDL-induced trained immunity. Our data reveal important aspects of LXR signaling in innate immunity with relevance to atherosclerosis formation.

Keywords: LXR; immunometabolism; inflammation; oxLDL; trained innate immunity

DOI: https://doi.org/10.3390/ijms23116166

WIREs Mech Dis. 2022 Jun 08. e1567

From infection to repair: Understanding the workings of our innate immune cells.

Martin Mawhinney, Amelia Kulle, Ajitha Thanabalasuriar.

In a world filled with microbes, some posing a threat to our body, our immune system is key to living a healthy life. The innate immune system is made of various cell types that act to guard our bodies. Unlike the adaptive immune system that has a specific response, our innate immune system encompasses cells that elicit unspecific immune responses, triggered whenever the right signals are detected. Our understanding of immunity started with the concept of our immune system only responding to "nonself" like the pathogens that invade our body. However, over the past few decades, we have learned that the immune system is more than an on/off switch that recognizes nonself. The innate immune system regularly patrols our bodies for pathogens and tissue damage. Our innate immune system not only seeks to resolve infection but also repair tissue injury, through phagocytosing debris and initiating the release of growth factors. Recently, we are starting to see that it is not just recognizing danger, our innate immune system plays a crucial role in repair. Innate immune cells phenotypically change during repair. In the context of severe injury or trauma, our innate immune system is modified quite drastically to help repair, resulting in reduced infection control. Moreover, these changes in immune cell function can be modified by sex as a biological variable. From past to present, in this overview, we provide a summary of the innate immune cells and pathways in infection and tissue repair. This article is categorized under: Immune System Diseases > Molecular and Cellular Physiology.

Keywords: immunology; innate immune cells; sterile injury

DOI: https://doi.org/10.1002/wsbm.1567

Atherosclerosis. 2022 May 25. pii: S0021-9150(22)00251-9. [Epub ahead of print]352 35-45

Cholesterol crystals drive metabolic reprogramming and M1 macrophage polarisation in primary human macrophages.

Sinead A O'Rourke, Nuno G B Neto, Eimear Devilly, Lianne C Shanley, Hannah K Fitzgerald, Michael G Monaghan, Aisling Dunne.

BACKGROUND AND AIMS: Metabolic reprogramming of innate immune cells is emerging as a key player in the progression of a number of chronic diseases, including atherosclerosis, where high rates of glycolysis correlate with plaque instability. This study aimed to investigate if cholesterol crystals, which are key atherosclerosis-associated DAMPs (damage/danger-associated molecular patterns), alter immune cell metabolism and whether this, in turn, impacts on macrophage phenotype and function.METHODS AND RESULTS: Primary human macrophages were treated with cholesterol crystals and expression of M1 (CXCL9, CXCL10) and M2-associated (MRC1, CCL13) macrophage markers, alarmins, and inflammatory cytokines were assessed either by real-time PCR or ELISA. Cholesterol crystal-induced changes in glycolytic markers were determined using real-time PCR and western blotting, while changes in cellular respiration and mitochondrial dynamics were examined via Seahorse analysis, Fluorescence Lifetime Imaging Microscopy (FLIM) and confocal microscopy. Treatment of macrophages with cholesterol crystals upregulated mRNA levels of CXCL9 and CXCL10, while concomitantly downregulating expression of MRC1 and CCL13. Cholesterol crystal--treated macrophages also exhibited a significant shift in metabolism to favour glycolysis, accompanied by the expression of key glycolytic markers GLUT1, Hexokinase 2, HIF1α, GAPDH and PFKFB3. Furthermore, we show that these effects are mediated upstream by the glycolytic enzyme, PKM2, and that direct inhibition of glycolysis or PKM2 nuclear localisation leads to a significant reduction in cholesterol crystal-induced inflammatory readouts.
CONCLUSIONS: This study not only provides further insight into how atherosclerosis-associated DAMPs impact on immune cell function, but also highlights metabolic reprogramming as a potential therapeutic target for cholesterol crystal-related inflammation.

Keywords: Atherosclerosis; Cardiovascular disease; Immunometabolism; Inflammation; Innate immunity; Macrophages; Metabolic reprogramming

DOI: https://doi.org/10.1016/j.atherosclerosis.2022.05.015