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Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

ABSTRACT: Acute myocardial infarction (MI) induces an extensive sterile inflammation, which is dominated in the early phase by invading neutrophils and monocytes/macrophages. The inflammatory response after MI critically affects infarct healing and cardiac remodeling. Therefore, modulation of cardiac inflammation may improve outcome post MI. Insulin-like growth factor 1 (IGF1) treatment reduces infarct size and improves cardiac function after MI via IGF1 receptor mediated signaling in myeloid cells. Our study aimed to investigate the effect of IGF1 on neutrophil phenotype both in vitro and in vivo after MI. We show that IGF1 induces an anti-inflammatory phenotype in bone marrow derived neutrophils. On the molecular and functional level IGF1 treated neutrophils were indistinguishable from those induced by IL4. Surprisingly, insulin, even though it is highly similar to IGF1 did not create anti-inflammatory neutrophils. Notably, the IGF1 effect was independent of the canonical Ras/Raf/ERK or PI3K/AKT pathway, but depended on activation of the JAK2/STAT6 pathway, which was not activated by insulin treatment. Single cell sequencing analysis 3 days after MI also showed that 3 day IGF1 treatment caused a downregulation of pro-inflammatory genes and upstream regulators in most neutrophil and many macrophage cell clusters whereas anti-inflammatory genes and upstream regulators were upregulated. Thus, IGF1 acts like an anti-inflammatory cytokine on myeloid cells in vitro and attenuates the pro-inflammatory phenotype of neutrophils and macrophages in vivo after MI. IGF1 treatment might therefore represent an effective immune modulatory therapy to improve the outcome after MI.

SUBMITTER: Nederlof R

PROVIDER: S-EPMC9334797 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

Nederlof Rianne R Reidel Sophia S Spychala André A Gödecke Stefanie S Heinen André A Lautwein Tobias T Petzsch Patrick P Köhrer Karl K Gödecke Axel A

Frontiers in immunology 20220715

Acute myocardial infarction (MI) induces an extensive sterile inflammation, which is dominated in the early phase by invading neutrophils and monocytes/macrophages. The inflammatory response after MI critically affects infarct healing and cardiac remodeling. Therefore, modulation of cardiac inflammation may improve outcome post MI. Insulin-like growth factor 1 (IGF1) treatment reduces infarct size and improves cardiac function after MI <i>via</i> IGF1 receptor mediated signaling in myeloid cells ...[more]

PMID: 35911749

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Project description:BackgroundSphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze proapoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase to produce the prosurvival molecule sphingosine-1-phosphate. We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI.MethodsWe performed transcriptomic, sphingolipid, and protein analyses to evaluate sphingolipid metabolism and signaling post-MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA [modRNA]) of AC function post hypoxia or MI.ResultsWe found that several genes involved in de novo ceramide synthesis were upregulated and that ceramide (C16, C20, C20:1, and C24) levels had significantly increased 24 hours after MI. AC inhibition after hypoxia or MI resulted in reduced AC activity and increased cell death. By contrast, enhancing AC activity via AC modRNA treatment increased cell survival after hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival, and smaller scar size than control mice 28 days post-MI. We attributed the improvement in heart function post-MI after AC modRNA delivery to decreased ceramide levels, lower cell death rates, and changes in the composition of the immune cell population in the left ventricle manifested by lowered abundance of proinflammatory detrimental neutrophils.ConclusionsOur findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post-MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.

Project description:Inflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway. nflammatory response plays a bidirectional regulatory role in myocardial infarction (MI). TLR signaling pathway plays an important role in the development of inflammation. Additionally, we discovered that CCRR is an anti-arrhythmic lncRNA in a prior work. Here we show, it is decreased in mice with 3-day MI followed by a sharp increase of pro-inflammatory cytokines and activation of the TLR pathway. Overexpression of CCRR could effectively inhibit the inflammatory response, reduce the infarct area, and improve cardiac function. And also reduced hypoxia-induced inflammation in cardiomyocytes and macrophages induced by IFN and LPS. It produced a similar protective effect in cardiomyocytes co-cultured with macrophages. Through microarray analysis, RNA-binding protein immunoprecipitation analysis, and other related experiments verification, TLR2 and TLR4 may be as potential targets of CCRR after MI. Our findings provide the evidence that lncRNA CCRR plays a key cardioprotective role against MI injury by targeting the TLR signaling pathway.

Project description:BackgroundNeutrophils play crucial roles in the inflammatory response after acute cerebral infarction (ACI). Previous studies revealed neutrophils are non-homogeneous and can be divided into at least two subtypes, pro-inflammatory and anti-inflammatory, correlated with patients' prognosis.ObjectiveWe aimed to explore the correlation between disease severity and peripheral blood neutrophils in patients with ACI and determine whether remote ischemic postconditioning (RIPostC) exerts neuroprotective effects by regulating neutrophils.MethodsPatients (n = 38) with acute anterior circulation cerebral infarction were assigned to conventional treatment (n = 24; included aspirin, statins, neuro nutrition drugs, and circulation improvement drugs) or RIPostC (n = 14; 7-day ischemia adaptation [complete ischemia of both upper extremities for 5 minutes followed by remission for 5 minutes, 5 repeated cycles, twice a day, started from the morning of the second day of admission] based on conventional treatment) groups, based on their preference. General clinical data and peripheral blood samples were taken three times, in the morning before and 3 and 7 days after treatment. Fifteen adults with non-acute cerebral infarction matched for sex, age, and risk factors were recruited as controls; peripheral blood samples were only collected on the recruitment day. We used flow cytometry to detect the percentage of neutrophils and Real-Time PCR to detect the gene expression of interleukin (IL)-1β in the peripheral blood samples.ResultsThe percentage of neutrophils, pro-inflammatory neutrophils (IL-1β high expression in flow cytometry), and IL-1β mRNA expression increased after ACI (P = 0.01, P = 0.001, P < 0.001). The National Institutes of Health Stroke Scale (NIHSS) score of patients with ACI within one day of onset was positively correlated with the percentage of pro-inflammatory neutrophils (R = 0.618, P = 0.043). Pro-inflammatory neutrophils in the RIPostC group decreased compared with those in the conventional treatment group, with the most significant difference observed on Day 7 (P = 0.01). However, the percentage of neutrophils was not statistically different. IL-1β mRNA expression decreased, with the most significant difference on Day 3 (P = 0.004). The NIHSS and Modified Rankin Scale scores for RIPostC decreased more significantly than for conventional treatment (P = 0.002, P = 0.019).ConclusionMore severe cerebral infarction was associated with a higher percentage of pro-inflammatory neutrophils. The neuroprotective effect of RIPostC may partly be exerted through gene regulation to reduce pro-inflammatory neutrophils.

Dataset Information

Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

Publications

Insulin-Like Growth Factor 1 Attenuates the Pro-Inflammatory Phenotype of Neutrophils in Myocardial Infarction.

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