Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, the consequences of an alternate high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue concerning common situations where dietary habits change over time, we developed a novel protocol in athero-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, the overall period of time of exposure to HFD being similar between groups. We showed that alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe-/- mice compared to continuous HFD. The pro-atherogenic effect of alternate HFD was also found in Apoe-/-Rag2-/- mice lacking T, B, and NKT cells, ruling out a role for the adaptive immune system in the observed phenotype. Using different complementary in vivo approaches, we found that lipid-rich diet discontinuation in alternate group downregulated Runx1, a negative regulator downstream of TLR-4 pathways. As a result, after re-exposure to HFD, myeloid progenitors were more sensitive to hypercholesterolemia leading to acute differentiation into IL-1b- producing immature neutrophils, which caused a state of emergency myelopoiesis. Consecutively, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1b receptor confirmed that the IL-1b signaling pathway was a major driver of the pro-inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1b neutralizing antibody or inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1b-dependent neutrophil progenitor reprogramming.

Project description:Systemic immune responses induced by chronic hypercholesterolemia contribute to the initiation, progression and complications of atherosclerosis. However, it is common for individuals to change dietary habits over time. The consequences of an alternating high fat diet and the associated variations in plasma cholesterol levels on atherosclerosis are unknown. To address this relevant issue, we developed a novel protocol in atherosclerosis-prone mice that allowed us to compare the effects of alternate versus continuous high fat diet (HFD) on atherosclerosis, while keeping the overall period of exposure to HFD similar between groups. We showed that an alternate HFD lead to accelerated atherosclerosis in Ldlr-/- and Apoe 55 -/- mice compared to continuous HFD. This pro-atherogenic effect of alternate HFD was also observed in Apoe-/-Rag2 57 -/- mice lacking T, B, and NKT cells, ruling out the role of the adaptive immune system in the observed phenotype. Employing various complementary in vivo approaches, we discovered that discontinuing HFD in the alternate group downregulated Runx1, a negative regulator of inflammatory signaling pathways in the myeloid lineage. Consequently, after re61 exposure to HFD, myeloid progenitors were primed to respond to HFD re-exposure by differentiating into IL-1-producing immature neutrophils, and inducing a state of emergency myelopoiesis. Subsequently, neutrophils markedly increased in the peripheral blood, infiltrated atherosclerotic lesions and locally released neutrophil extracellular traps. Anti-Ly6G neutrophil depletion abolished the pro-atherogenic effects of alternate HFD. Specific deletion of Il1b and Il1 receptor confirmed that the IL-1 signaling pathway was a major driver of the pro67 inflammatory and pro-atherogenic neutrophil signature. Finally, treatment with anti-IL-1 neutralizing antibody or an inflammasome inhibitor during re-exposure to HFD reversed the pro-atherogenic effects of alternate HFD. In summary, we showed that alternate HFD accelerates atherosclerosis through IL-1-dependent neutrophil progenitor reprogramming.

Project description:Background: Sustained sleep insufficiency impairs immune system and increases the adverse outcomes of cardiovascular diseases. However, the role and mechanisms prolonged sleep fragmentation (SF) on the outcomes of myocardial infarction (MI) remains elusive. Methods: Among 497 MI patients with complete sleep data participating in the National Health and Nutrition Examination Survey, the association between different types of sleep disorders and post-MI survivability was evaluated. We then developed a mouse model with 10 weeks of SF followed by MI surgery. Emergency hematopoiesis and neutrophil expansion were analyzed. Potential mechanisms were explored using bone marrow (BM) transplantation, anti-SiglecF neutralizing antibodies and Interferon alpha and beta receptor subunit 1 knockout (Ifnar1-/-) in BM. Results: Frequent nocturnal awakening independently predicted reduced survival rate of MI patients, with a hazard ratio (HR) of 2.136 (95% CI=1.142-3.995). Increased infarct size, deteriorated cardiac function and lower survival rate were also observed in MI mice pretreated with 10-week SF. SF facilitated post-MI neutrophil expansion and infiltration into infarct area, differentiating into SiglecFhi subset. Inhibition of SiglecFhi neutrophils allowed for the alleviations of post-MI cardiac remodeling. Furthermore, BM progenitors were skewed toward neutrophil lineage concomitant with the clonal expansion of granulocyte-monocyte progenitors (GMPs) in MI mice pretreated with 10-week SF. Transcriptome analysis and functional experiments revealed that activation of type I interferon (IFN) signaling was involved in this process, while depletion of Ifnar1 in BM and administration of IFNAR1-neutralizing antibodies significantly alleviated post-MI cardiac remodeling and neutrophil expansion. Conclusions: SF aggravates post-MI cardiac remodeling and dysfunction through promoting GMP differentiation and neutrophil expansion. Blockage of type I IFN could alleviate this detrimental influence.

Project description:The advent of recent cutting-edge technologies has allowed the discovery and characterization of novel hematopoietic progenitors, including SSCloCD66b+CD15+CD11b-CD49dhiproNeu1s and SSChiCD66b+CD15+CD11b-CD49dintproNeus2s, CD66b+CD15+CD11b+CD49d+CD101-preNeus and Lin-CD66b+CD117+CD71+eNePs along human neutropoiesis process. In this research field, we recently identified CD66b-CD38+CD64dimCD115-, CD34+ and CD34dim/-cells exclusively committed to the neutrophil lineage [which we renamed as CD34+ and CD34dim/- neutrophil-committed progenitors (NCPs)], representing the earliest neutrophil precursors identifiable and sorted by flow cytometry. Moreover, based on their differential CD34 and CD45RA expression, we could identify four populations of NCPs, namely: CD34+CD45RA-/NCP1s, CD34+CD45RA+/NCP2s, CD34dim/-CD45RA+/NCP3s and CD34dim/-CD45RA-/NCP4s. This said, a very recent study by Ikeda and coworkers (PMID: 36862552) reported that neutrophil precursors termed either neutrophil progenitors (NePs) or “early neutrophil-committed progenitors” would generate immunosuppressive neutrophil-like CXCR1+CD14+CD16-monocytes. Hence, presuming that NePs/alias “early neutrophil-committed progenitors” correspond to NCPs, the selective neutrophil-commitment that we attributed to NCPs is contradicted by Ikeda and coworkers’ paper. In this study, by performing a more analytical reevaluation at the phenotypic and molecular levels of the cells generated by NCP2s and NCP4s (selected as representatives of NCPs), we categorically exclude that NCPs generate neutrophil-like CXCR1+CD14+CD16-monocytes. Rather, we provide substantial evidence indicating that the cells generated by NePs/alias “early neutrophil-committed progenitors” are neutrophilic cells at different stage of maturation, displaying moderate levels of CD14, instead of neutrophil-like CXCR1+CD14+CD16-monocytes as pointed by Ikeda and coworkers. Hence, the conclusion that NePs/alias “early neutrophil-committed progenitors” aberrantly differentiate into neutrophil-like monocytes derives, in our opinion, from data misinterpretation

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Alternate high fat diet aggravates atherosclerosis through an IL1B- 2 dependent reprogramming of neutrophil progenitors

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