Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides

Neidhart, Michel; Pająk, Agnieszka; Laskari, Katerina; Riksen, Niels P.; Joosten, Leo A. B.; Netea, Mihai G.; Lutgens, Esther; Stroes, ES; Ciurea, Adrian; Distler, Oliver; Grigorian, Mariam; Karouzakis, Emmanuel

doi:10.3389/fimmu.2019.00791

Cited by 37 publications

(18 citation statements)

References 45 publications

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“…Moreover, in a mouse model of atherosclerosis (ApoE −/− mice), short-term treatment of lipopolysaccharide (LPS) in a super-low-dose that mimics chronic infection elicits the polarization of monocytes into a sustained pro-inflammatory state with upregulated Ly6C, CCR5, MCP-1, and decreased SR-B1 expression level, and the result of which is the aggravation of atherosclerosis (27). In addition to microbial stimuli, recent findings demonstrated that several non-microbial endogenous products, which have been associated with ASCVD, can also induce trained immunity in monocytes/macrophages (26,(28)(29)(30). Notably, training of monocytes by these compounds including oxLDL, lipoprotein(a), aldosterone, and the oligomeric S100A4 induces a pro-inflammatory and pro-atherogenic phenotype.…”

Section: Pro-atherogenic Effect Of Trained Immunitymentioning

confidence: 99%

“…Notably, training of monocytes by these compounds including oxLDL, lipoprotein(a), aldosterone, and the oligomeric S100A4 induces a pro-inflammatory and pro-atherogenic phenotype. Firstly, the primed monocytes show an enhanced ability of vascular endothelial adhesion and transmigration (28) as well as an increased production of pro-inflammatory cytokines upon re-stimulation by Toll-like receptor (TLR) agonists (26,(28)(29)(30). Besides, the cholesterol-laden foam cell formation and the expression of matrix metalloproteinases, which have been implicated in the progression of atherosclerosis, are both significantly accelerated in oxLDL-trained macrophages (26).…”

Section: Pro-atherogenic Effect Of Trained Immunitymentioning

confidence: 99%

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Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

et al. 2020

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Atherosclerosis, a chronic inflammatory disease of the arterial wall, is among the leading causes of morbidity and mortality worldwide. The persistence of low-grade vascular inflammation has been considered to fuel the development of atherosclerosis. However, fundamental mechanistic understanding of the establishment of non-resolving low-grade inflammation is lacking, and a large number of atherosclerosis-related cardiovascular complications cannot be prevented by current therapeutic regimens. Trained immunity is an emerging new concept describing a prolonged hyperactivation of the innate immune system after exposure to certain stimuli, leading to an augmented immune response to a secondary stimulus. While it exerts beneficial effects for host defense against invading pathogens, uncontrolled persistent innate immune activation causes chronic inflammatory diseases. In light of the above, the long-term over-activation of the innate immune system conferred by trained immunity has been recently hypothesized to serve as a link between non-resolving vascular inflammation and atherosclerosis. Here, we provide an overview of current knowledge on trained immunity triggered by various exogenous and endogenous inducers, with particular emphasis on its pro-atherogenic effects and the underlying intracellular mechanisms that act at both the cellular level and systems level. We also discuss how trained immunity could be mechanistically linked to atherosclerosis from both preclinical and clinical perspectives. This review details the mechanisms underlying the induction of trained immunity by different stimuli, and highlights that the intracellular training programs can be different, though partly overlapping, depending on the stimulus and the biological system. Thus, clinical investigation of risk factor specific innate immune memory is necessary for future use of trained immunity-based therapy in atherosclerosis.

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Section: Pro-atherogenic Effect Of Trained Immunitymentioning

confidence: 99%

Section: Pro-atherogenic Effect Of Trained Immunitymentioning

confidence: 99%

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

et al. 2020

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“…Whilst prior LPS exposure can "tolerize" monocytes to future stimulation, we propose that the presence of GM-CSF may prevent or have the opposite effect, driving monocyte "training" to enhance subsequent cytokine responses. Such an effect has recently been shown for S100 proteins in inflammatory arthritis (14).…”

Section: Discussionmentioning

confidence: 55%

GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis

et al. 2020

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Objectives: GM-CSF is a pro-inflammatory cytokine with multiple actions predominantly on myeloid cells. Enhanced GM-CSF expression by lymphocytes from patients with Ankylosing Spondylitis (AS) has recently been described, however, its potential pathogenic role(s) in AS are unknown. Methods: The effects of GM-CSF on TNF, IL-23, and CCL17 production by blood, PBMCs and isolated CD14+ monocytes from AS patients and healthy controls (HCs) were studied using ELISA. Serum CCL17 and GM-CSF and T cell GM-CSF production were studied in AS patients including pre-and on TNFi therapy. Results: GM-CSF markedly increased TNF production by LPS-stimulated whole blood, peripheral blood mononuclear cells (PBMC) and purified monocytes from AS patients, with 2 h GM-CSF exposure sufficient for monocyte "priming." Blocking of GM-CSF significantly reduced the production of TNF by whole blood from AS patients but not HCs. GM-CSF priming increased IL-23 production from LPS-stimulated AS and HC whole blood 5-fold, with baseline and stimulated IL-23 levels being significantly higher in AS whole blood. GM-CSF also stimulated CCL17 production from AS and HC blood and CCL17 levels were elevated in AS plasma. GM-CSF could be detected in plasma from 14/46 (30%) AS patients compared to 3/18 (17%) HC. Conclusion: We provide evidence that GM-CSF primes TNF and IL-23 responses in myeloid cells from AS patients and HC. We also show CCL17 levels, downstream of GM-CSF, were elevated in plasma samples of AS patients. Taken together these observations are supportive of GM-CSF neutralization as a potential novel therapeutic approach for the treatment of AS.

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“…Macrophages may be tolerant to LPS, an effect that lasts for a period of time. [31] To explore how macrophages become tolerance to LPS, we observed the effects of melatonin and LPS on macrophage polarization. As expected, repeated LPS treatment led to macrophage tolerance of LPS (Fig.…”

Section: Melatonin Reverses the Macrophage Tolerance Of Lpsmentioning

confidence: 99%

Melatonin Maintains Macrophage M1 Phenotype to Reverse LPS-stimulated Tumor Immune Tolerance

Lin

Zhang

Zhou

et al. 2020

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Background: Lipopolysaccharide (LPS) is a potent trigger of macrophage-mediated inflammation and its repeated stimulation results in immune tolerance. This study is to explore the cellular mechanisms of LPS-mediated tumor immune tolerance and to investigate whether melatonin can reverse this tolerance. Methods: The effect of melatonin and LPS on macrophages was assessed by cell proliferation, morphological changes, phagocytosis and autophagy in vitro. The tumor-preventing effect of melatonin and LPS were evaluated in the urethane-induced lung carcinoma model and in the H22 liver cancer allograft model. Immunofluorescence, immunohistochemistry and ELISA were used to examine protein expression. The related targets and pathways of melatonin were predicted by comprehensive bioinformatics, and the clinical association of bacterial infections and survival was evaluated in cancer patients by meta-analysis.Results: In vitro，Raw264.7 macrophages were polarized toward the M1 phenotype by single LPS administration but toward the M2 phenotype by repeated LPS administration. Interestingly, combination treatment with repeated LPS and 10 µM melatonin prevented macrophage polarization toward the M2-like phenotype and exerted lasting antitumor efficacy. In the urethane-induced lung carcinoma model, repeated LPS administration stimulated macrophage polarization toward the M2 phenotype and promoted lung carcinogenesis, which was abrogated by macrophage depletion, while melatonin alone or in combination with repeated LPS challenge restored M1-like macrophages and prevented carcinogenesis. In the H22 liver cancer allograft model, melatonin maintained the macrophage phenotype and promoted the tumor-suppressing effect of repeated LPS challenge. Furthermore, we found that macrophages repeatedly stimulated with LPS had a high level of surface lipid rafts that mediated PI3K/AKT and JAK2/STAT3 signaling and prevented both LPS sensitivity and immune response by self-expression of PD-L1 and surface expression of PD-1 receptor on NK cells, whereas melatonin decreased surface lipid rafts and PI3K/AKT and JAK2/STAT3 signaling. Finally, we conducted a comprehensive bioinformatics analysis of melatonin-relevant targets and pathways involved in M2 macrophage polarization and evaluated the clinical associations of bacterial infections and survival in cancer patients. Conclusions: This study suggests a function of melatonin in regulating macrophage polarization to maintain LPS-stimulated tumor immune surveillance.

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Oligomeric S100A4 Is Associated With Monocyte Innate Immune Memory and Bypass of Tolerance to Subsequent Stimulation With Lipopolysaccharides

Cited by 37 publications

References 45 publications

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

Trained Immunity: An Underlying Driver of Inflammatory Atherosclerosis

GM-CSF Primes Proinflammatory Monocyte Responses in Ankylosing Spondylitis

Melatonin Maintains Macrophage M1 Phenotype to Reverse LPS-stimulated Tumor Immune Tolerance

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