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β2 adrenergic receptors orchestrate neutrophil demargination and recruitment to the ischemic heart following myocardial infarction- 2nd mass spectrometry study

ABSTRACT: Neutrophils play a crucial role in instigating inflammation as well as its resolution postmyocardial infarction (MI). Although granulopoiesis in the bone marrow (BM) is the major source of cardiac neutrophils post-MI, infiltration of neutrophils to the heart occurs much quicker than peak granulopoiesis. Using a combination of flow cytometry, BM ablation of hematopoietic stem cells, confocal microscopy and multiple proteomics analysis, we found that the first wave of neutrophils recruited to the ischemic heart is exclusively sourced from vasculature and not from granulopoiesis in the BM/ spleen. The MIevoked neutrophilia during the early hours bore all hallmarks of demargination induced by classical demarginating agents such as dexamethasone/ norepinephrine (NE). Various pharmacological and genetic strategies aimed at suppressing NE synthesis or disruption of β-AR signaling reduced both neutrophil demargination as well as recruitment to the heart. Interestingly, however, despite a marked reduction in cardiac neutrophil burden only short-term inhibition of β-ARs improved cardiac remodeling and function. Our findings support a pharmacological strategy to contain the initial onslaught of neutrophils on the ischemic heart using β2-AR blockers to regulate the otherwise runaway inflammatory response.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Neutrophil

DISEASE(S): Myocardial Ischemia

SUBMITTER: Felicia Antohe

LAB HEAD: Felicia Antohe

PROVIDER: PXD074944 | Pride | 2026-03-20

REPOSITORIES: Pride

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			Action	DRS
	060723_70581_CTRL1_1ug.raw	Raw
	060723_70581_CTRL2_1ug.raw	Raw
	060723_70581_CTRL3_1ug.raw	Raw
	060723_70581_CTRL4_1ug.raw	Raw
	060723_70581_NE1_1ug.raw	Raw

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Project description:Acute myocardial infarction (AMI) induces a rapid and robust inflammatory response characterized by infiltration of different immune cell types to the infarcted heart. The recruitment of immune cells is a dynamic process and consists of sequential infiltration of neutrophils, proand anti-inflammatory monocytes, and lymphocytes to the injured myocardium. neutrophils are the first responders to ischemic injury and have the ability to amplify the initial inflammatory response by deploying key alarmins such as S100A8 and S100A9. These alarmins interact with Toll-Like-Receptor (TLR4) on naïve neutrophils, prime the NLRP3 inflammasome and facilitate their migration to the bone marrow (BM). The reverse-migrated neutrophils are preferentially retained within the BM sinusoids by certain adhesion receptors, a process that is essential for the activation of Gasdermin D- dependent membrane pore formation and secretion of IL-1β. Under steady-state conditions, mature neutrophils are present in major reservoirs across the body (spleen, liver, BM, lungs, and vasculature) and are recruited following changes in homeostasis. The unique feature of neutrophils in the vasculature is their distribution into two distinct groups, the marginated and the demarginated. Firmly adherent to the vasculature walls, the marginated pool of neutrophils represents ~ 51% of neutrophils in circulation and are believed to serve as early responders. The demargination process in neutrophils is attributed to loss of adhesion molecules, and rearrangement of actin cytoskeleton within the cells. Under certain stress and inflammatory conditions, adhesion of neutrophils is altered, and the marginated cells detach and mobilize into the bloodstream, expanding the percentage of demarginated cells in the blood. We reasoned that the marginated pool of neutrophils may be mobilized to meet the sudden and increased demand of the ischemic heart. Thus, deciphering the signaling pathways that stimulate the demargination of neutrophils and their recruitment to the ischemic heart may provide a viable approach to regulate neutrophil trafficking to the heart post-MI.

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.

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β2 adrenergic receptors orchestrate neutrophil demargination and recruitment to the ischemic heart following myocardial infarction- 2nd mass spectrometry study

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