bims-traimu 2023-05-21 papers

Issue of 2023–05–21
five papers selected by
Yantong Wan, Southern Medical University

Immunometabolism (Cobham). 2023 Apr;5(2): e00021

A new frontier for fat: dietary palmitic acid induces innate immune memory.

Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.

Keywords: CD36; ceramide; chylomicron; epigenetics; hematopoietic stem cell; inflammation; innate immune memory; ketogenic diet; macrophages; metabolism; monocytes; oleic acid; palmitic acid; priming; saturated fatty acid; toll-like receptor; trained immunity; western diet

DOI: https://doi.org/10.1097/IN9.0000000000000021

Newborn (Clarksville). 2023 Jan-Mar;2(1):2(1): 60-79

Innate Immune Memory in Macrophages.

Akhil Maheshwari.

Macrophages have been recognized as the primary mediators of innate immunity starting from embryonic/fetal development. Macrophage-mediated defenses may not be as antigen-specific as adaptive immunity, but increasing information suggests that these responses do strengthen with repeated immunological triggers. The concept of innate memory in macrophages has been described as "trained immunity" or "innate immune memory (IIM)." As currently understood, this cellular memory is rooted in epigenetic and metabolic reprogramming. The recognition of IIM may be particularly important in the fetus and the young neonate who are yet to develop protective levels of adaptive immunity, and could even be of preventive/therapeutic importance in many disorders. There may also be a possibility of therapeutic enhancement with targeted vaccination. This article presents a review of the properties, mechanisms, and possible clinical significance of macrophage-mediated IIM.

Keywords: Chromatin; Development; Fetus; Fumarate; Lipoprotein(a); MMP-2; MMP-9; Neonate; Newborn; Succinic acid; α-ketoglutaric acid

DOI: https://doi.org/10.5005/jp-journals-11002-0058

Mol Nutr Food Res. 2023 May 17. e2200845

"Negative regulation of innate immune signalling by components of the button mushroom Agaricus bisporus".

Michele O'Sullivan, Elaine Dempsey, Sarah Case, Emer E Hackett, Anna Ledwith, Hannah Prendeville, Tara O'Brien, Faye Lewis, Dearbhla Murphy, Supriya Yadav, Jude Wilson, Sinead C Corr, Frederick J Sheedy.

SCOPE: Mushrooms are valued as an edible and medical resource for millennia. As macrofungi, they possess conserved molecular components recognized by innate immune cells like macrophages, yet unlike pathogenic fungi, they do not trigger the immune system in the same way. That these well-tolerated foods both avoid immuno-surveillance and have positive health benefits, highlights the dearth of information on the interactions of mushroom-derived products with our immune system.
METHODS & RESULTS: Using powders produced from the common white button mushroom, Agaricus bisporus, it was observed that pre-treatment of mouse and human macrophages with mushroom powders attenuates innate immune signalling triggered by microbial ligands like LPS and β-glucans, including NFκB activation and pro-inflammatory cytokine production. This effect of mushroom powders is observed at lower doses of TLR ligands, suggesting a model of competitive inhibition whereby mushroom compounds bind and occupy innate immune receptors, precluding activation by microbial stimuli. This effect is preserved following simulated digestion of the powders. Moreover, in-vivo delivery of mushroom powders attenuates the development of colitis in a DSS-mouse model.
CONCLUSION: Our data highlights an important anti-inflammatory role for powdered A. bisporus mushrooms, which could be further utilized to develop complementary approaches to modulate chronic inflammation and disease. This article is protected by copyright. All rights reserved.

Keywords: Dectin-1; inflammation; macrophage; mushroom; β-glucan

DOI: https://doi.org/10.1002/mnfr.202200845

Brain Sci. 2023 Mar 25. pii: 549. [Epub ahead of print]13(4):

Lipopolysaccharide Preconditioning Restricts Microglial Overactivation and Alleviates Inflammation-Induced Depressive-like Behavior in Mice.

Haiping Yu, Junli Kan, Mingming Tang, Yanbing Zhu, Baoyang Hu.

Overactive microglia and severe neuroinflammation play crucial roles in the development of major depressive disorder. Preconditioning with lipopolysaccharide (LPS) provides protection against severe neuroinflammation. However, administering high doses of LPS to mice triggers depressive symptoms. Therefore, the optimal dose of LPS preconditioning needs to be determined by further experiments. LPS preconditioning is an effective agent in anti-inflammation and neuroprotection, but the mechanism by which LPS preconditioning acts in depression remain unclear. This study finds that the anti-inflammation mechanism of low-dose LPS preconditioning is mainly dependent on G-protein-coupled receptor 84 (GPR84). We use low-dose LPS for preconditioning and re-challenged mice or BV2 microglia with high-dose LPS. In addition, RNA-seq is used to explore underlying changes with LPS preconditioning. Low-dose LPS preconditioning reduces the expression of pro-inflammatory mediators and inhibits microglial activation, as well as suppresses the depressive-like behavior when the mice are re-challenged with high-dose LPS. Further investigation reveals that the tolerance-like response in microglia is dependent on the GPR84. Here, we show that low-dose LPS preconditioning can exert anti-inflammation effects and alleviates inflammation-induced depressive-like behavior in mice. As a potential therapeutic target for depression, LPS preconditioning needs to be given further attention regarding its effectiveness and safety.

Keywords: G-protein-coupled receptor 84 (GPR84); LPS; depression; microglia; mouse model of inflammation-induced depression; neuroinflammation

DOI: https://doi.org/10.3390/brainsci13040549

Microbiol Spectr. 2023 May 16. e0429322

Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.

Minh-Thu Nguyen, Zhicheng Hu, Majd Mohammad, Hannah Schöttler, Silke Niemann, Michelle Schultz, Katarzyna Barczyk-Kahlert, Tao Jin, Heiko Hayen, Mathias Herrmann.

Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward the fermentative pathway, as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion, and lactate and malate accumulation than P3C. These observed P2C effects were completely abrogated in monocyte/macrophage-depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease.

Keywords: Pam2Cys; Pam3Cys; bacterial lipoprotein; bone erosion; bone marrow-derived macrophages; cellular metabolism; lactate

DOI: https://doi.org/10.1128/spectrum.04293-22