scholarly journals Exosome-Mediated eCIRP Release From Macrophages to Induce Inflammation in Sepsis

2021 ◽  
Vol 12 ◽  
Author(s):  
Atsushi Murao ◽  
Chuyi Tan ◽  
Alok Jha ◽  
Ping Wang ◽  
Monowar Aziz
Keyword(s):  
Rna Binding ◽  
Neutrophil Migration ◽  
Cecal Ligation ◽  
Neutrophil Infiltration ◽  
Mouse Serum ◽  
Macrophage Culture ◽  
Molecular Pattern ◽  
Serum Exosomes ◽  
Lps Treatment

Extracellular cold-inducible RNA-binding protein (eCIRP) is an important damage-associated molecular pattern (DAMP). Despite our understanding of the potentially harmful effects of eCIRP in sepsis, how eCIRP is released from cells remains elusive. Exosomes are endosome-derived extracellular vesicles, which carry proteins, lipids, and nucleic acids to facilitate intercellular communication and several extracellular functions. We hypothesized that eCIRP is released via exosomes to induce inflammation in sepsis. Exosomes isolated from the supernatants of LPS-treated macrophage culture and serum of endotoxemia and polymicrobial sepsis mice showed high purity, as revealed by their unique median sizes ranging between 70 and 126 nm in diameter. eCIRP levels of the exosomes were significantly increased after LPS treatment in the supernatants of macrophage culture, mouse serum, and cecal ligation and puncture (CLP)-induced sepsis mouse serum. Protease protection assay demonstrated the majority of eCIRP was present on the surface of exosomes. Treatment of WT macrophages and mice with exosomes isolated from LPS-treated WT mice serum increased TNFα and IL-6 production. However, treatment with CIRP−/- mice serum exosomes significantly decreased these levels compared with WT exosome-treated conditions. CIRP−/- mice serum exosomes significantly decreased neutrophil migration in vitro compared with WT exosomes. Treatment of mice with serum exosomes isolated from CIRP−/- mice significantly reduced neutrophil infiltration into the peritoneal cavity. Our data suggest that eCIRP can be released via exosomes to induce cytokine production and neutrophil migration. Thus, exosomal eCIRP could be a potential target to inhibit inflammation.

scholarly journals Extracellular CIRP decreases Siglec-G expression on B-1a cells skewing them towards a pro-inflammatory phenotype in sepsis

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
William Royster ◽  
Hui Jin ◽  
Ping Wang ◽  
Monowar Aziz
Keyword(s):  
Rna Binding ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Molecular Pattern ◽  
Tnf Α ◽  
Inflammatory Phenotype ◽  
Life Threatening ◽  
Natural Igm ◽  
Culture Supernatants

Abstract Background Sepsis is a life-threatening disease syndrome caused by a dysregulated host response to infection and injury. Extracellular cold-inducible RNA-binding protein (eCIRP) acts as a damage-associated molecular pattern. Peritoneal cavity (PerC) B-1a cells attenuate inflammation and tissue injury by spontaneous releasing natural IgM and IL-10. Sialic acid-binding immunoglobulin-type lectin-G (Siglec-G) is a CD33-related receptor highly expressed in B-1a cells to serve critical immunoregulatory functions. In sepsis, B-1a cell numbers in PerC are decreased. We hypothesized that eCIRP causes the reduction of PerC B-1a cells and alters their function during sepsis. Methods Sepsis was induced in WT and CIRP−/− mice by cecal ligation and puncture (CLP). PerC washout cells were collected and B-1a cells and Siglec-G were assessed by flow cytometry. Mice were i.p. injected with recombinant murine (rm) CIRP and after 20 h, Siglec-G expression in PerC B-1a cells were assessed. PerC B-1a cells were treated with rmCIRP for 4 h and Siglec-G expression was assessed. PerC B-1a cells were pre-treated with anti-Siglec-G Ab and then after stimulated with rmCIRP for 24 h, IL-6 levels in the culture supernatants were assessed. Results eCIRP levels in the PerC were elevated in septic mice. In WT mice, the frequencies and numbers of total and Siglec-G+ B-1a cells in the PerC were significantly decreased in the CLP group compared to sham group, whereas in CIRP−/− mice, their frequencies and numbers in sepsis were significantly rescued compared to WT septic mice. Mice injected with rmCIRP showed decreased frequencies and numbers of total and Siglec-G+ PerC B-1a cells compared to PBS-injected mice. In vitro treatment of PerC B-1a cells with rmCIRP demonstrated significant reduction in Siglec-G mRNA and protein compared to PBS group. PerC B-1a cells treated with anti-Siglec-G Ab had significantly higher production of IL-6 in response to rmCIRP compared to IgG control. Anti-Siglec-G Ab treated B-1a cells co-cultured with macrophages produced significantly higher levels of IL-6, and TNF-α, and lower levels of IL-10 compared to IgG-treated B-1a cells and macrophage co-cultures stimulated with rmCIRP. Conclusion eCIRP reduces PerC B-1a cell pool and skews them to a pro-inflammatory phenotype by downregulating Siglec-G expression. Targeting eCIRP will retain Siglec-G expressing B-1a cells in the PerC and preserve their anti-inflammatory function in sepsis.

scholarly journals Interaction with an endothelial lumen increases neutrophil lifetime and motility in response to P aeruginosa

Blood ◽  
2018 ◽  
Vol 132 (17) ◽  
pp. 1818-1828 ◽  
Author(s):  
Laurel E. Hind ◽  
Patrick N. Ingram ◽  
David J. Beebe ◽  
Anna Huttenlocher
Keyword(s):  
Endothelial Cells ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
3 Dimensional ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Neutrophil Survival ◽  
Pathogen Clearance

Abstract Neutrophil infiltration into tissues is essential for host defense and pathogen clearance. Although many of the signaling pathways involved in the transendothelial migration of neutrophils are known, the role of the endothelium in regulating neutrophil behavior in response to infection within interstitial tissues remains unclear. Here we developed a microscale 3-dimensional (3D) model that incorporates an endothelial lumen, a 3D extracellular matrix, and an intact bacterial source to model the host microenvironment. Using this system, we show that an endothelial lumen significantly increased neutrophil migration toward a source of Pseudomonas aeruginosa. Surprisingly, we found neutrophils, which were thought to be short-lived cells in vitro, migrate for up to 24 hours in 3D in the presence of an endothelial lumen and bacteria. In addition, we found that endothelial cells secrete inflammatory mediators induced by the presence of P aeruginosa, including granulocyte-macrophage colony-stimulating factor (GM-CSF), a known promoter of neutrophil survival, and interleukin (IL)-6, a proinflammatory cytokine. We found that pretreatment of neutrophils with a blocking antibody against the IL-6 receptor significantly reduced neutrophil migration to P aeruginosa but did not alter neutrophil lifetime, indicating that secreted IL-6 is an important signal between endothelial cells and neutrophils that mediates migration. Taken together, these findings demonstrate an important role for endothelial paracrine signaling in neutrophil migration and survival.

scholarly journals Proof-of-concept clinical trial of etokimab shows a key role for IL-33 in atopic dermatitis pathogenesis

2019 ◽  
Vol 11 (515) ◽  
pp. eaax2945 ◽  
Author(s):  
Yi-Ling Chen ◽  
Danuta Gutowska-Owsiak ◽  
Clare S. Hardman ◽  
Melanie Westmoreland ◽  
Teena MacKenzie ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Therapeutic Potential ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Severity Index ◽  
Fundamental Biology ◽  
Targeted Inhibition

Targeted inhibition of cytokine pathways provides opportunities to understand fundamental biology in vivo in humans. The IL-33 pathway has been implicated in the pathogenesis of atopy through genetic and functional associations. We investigated the role of IL-33 inhibition in a first-in-class phase 2a study of etokimab (ANB020), an IgG1 anti–IL-33 monoclonal antibody, in patients with atopic dermatitis (AD). Twelve adult patients with moderate to severe AD received a single systemic administration of etokimab. Rapid and sustained clinical benefit was observed, with 83% achieving Eczema Area and Severity Index 50 (EASI50), and 33% EASI75, with reduction in peripheral eosinophils at day 29 after administration. We noted significant reduction in skin neutrophil infiltration after etokimab compared with placebo upon skin challenge with house dust mite, reactivity to which has been implicated in the pathogenesis of AD. We showed that etokimab also inhibited neutrophil migration to skin interstitial fluid in vitro. Besides direct effects on neutrophil migration, etokimab revealed additional unexpected CXCR1-dependent effects on IL-8–induced neutrophil migration. These human in vivo findings confirm an IL-33 upstream role in modulating skin inflammatory cascades and define the therapeutic potential for IL-33 inhibition in human diseases, including AD.

Liver X Receptor Activation Impairs Neutrophil Functions and Aggravates Sepsis

2019 ◽  
Vol 221 (9) ◽  
pp. 1542-1553 ◽  
Author(s):  
Fabrício O Souto ◽  
Fernanda V S Castanheira ◽  
Silvia C Trevelin ◽  
Braulio H F Lima ◽  
Guilherme Cesar Martelossi Cebinelli ◽  
...  
Keyword(s):  
Multiorgan Failure ◽  
Bacterial Load ◽  
Cecal Ligation ◽  
Neutrophil Infiltration ◽  
Receptor Activation ◽  
Messenger Ribonucleic Acid ◽  
X Receptors ◽  
Lxr Agonists

Abstract Background Liver X receptors (LXRs) are nuclear receptors activated by oxidized lipids and were previously implicated in several metabolic development and inflammatory disorders. Although neutrophils express both LXR-α and LXR-β, the consequences of their activation, particularly during sepsis, remain unknown. Methods We used the model of cecal ligation and puncture (CLP) to investigate the role of LXR activation during sepsis. Results In this study, we verified that LXR activation reduces neutrophil chemotactic and killing abilities in vitro. Mice treated with LXR agonists showed higher sepsis-induced mortality, which could be associated with reduced neutrophil infiltration at the infectious foci, increased bacteremia, systemic inflammatory response, and multiorgan failure. In contrast, septic mice treated with LXR antagonist showed increased number of neutrophils in the peritoneal cavity, reduced bacterial load, and multiorgan dysfunction. More important, neutrophils from septic patients showed increased ABCA1 messenger ribonucleic acid levels (a marker of LXR activation) and impaired chemotactic response toward CXCL8 compared with cells from healthy individuals. Conclusions Therefore, our findings suggest that LXR activation impairs neutrophil functions, which might contribute to poor sepsis outcome.

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195 ◽  
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

Abstract The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

scholarly journals Metoprolol exerts a non-class effect against ischaemia–reperfusion injury by abrogating exacerbated inflammation

2020 ◽  
Vol 41 (46) ◽  
pp. 4425-4440 ◽  
Author(s):  
Agustín Clemente-Moragón ◽  
Mónica Gómez ◽  
Rocío Villena-Gutiérrez ◽  
Doménica V Lalama ◽  
Jaime García-Prieto ◽  
...  
Keyword(s):  
Conformational Changes ◽  
In Silico ◽  
Adrenergic Receptor ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Β Blockers

Abstract Aims Clinical guidelines recommend early intravenous β-blockers during ongoing myocardial infarction; however, it is unknown whether all β-blockers exert a similar cardioprotective effect. We experimentally compared three clinically approved intravenous β-blockers. Methods and results Mice undergoing 45 min/24 h ischaemia–reperfusion (I/R) received vehicle, metoprolol, atenolol, or propranolol at min 35. The effect on neutrophil infiltration was tested in three models of exacerbated inflammation. Neutrophil migration was evaluated in vitro and in vivo by intravital microscopy. The effect of β-blockers on the conformation of the β1 adrenergic receptor was studied in silico. Of the tested β-blockers, only metoprolol ameliorated I/R injury [infarct size (IS) = 18.0% ± 0.03% for metoprolol vs. 35.9% ± 0.03% for vehicle; P < 0.01]. Atenolol and propranolol had no effect on IS. In the three exacerbated inflammation models, neutrophil infiltration was significantly attenuated only in the presence of metoprolol (60%, 50%, and 70% reductions vs. vehicle in myocardial I/R injury, thioglycolate-induced peritonitis, and lipopolysaccharide-induced acute lung injury, respectively). Migration studies confirmed the particular ability of metoprolol to disrupt neutrophil dynamics. In silico analysis indicated different intracellular β1 adrenergic receptor conformational changes when bound to metoprolol than to the other two β-blockers. Conclusions Metoprolol exerts a disruptive action on neutrophil dynamics during exacerbated inflammation, resulting in an infarct-limiting effect not observed with atenolol or propranolol. The differential effect of β-blockers may be related to distinct conformational changes in the β1 adrenergic receptor upon metoprolol binding. If these data are confirmed in a clinical trial, metoprolol should become the intravenous β-blocker of choice for patients with ongoing infarction.

scholarly journals Tanshinone IIA Protects against Dextran Sulfate Sodium- (DSS-) Induced Colitis in Mice by Modulation of Neutrophil Infiltration and Activation

2016 ◽  
Vol 2016 ◽  
pp. 1-10 ◽  
Author(s):  
Xiaowei Liu ◽  
Haiyue He ◽  
Tingting Huang ◽  
Zhen Lei ◽  
Fuquan Liu ◽  
...  
Keyword(s):  
Dextran Sulfate ◽  
Dextran Sulfate Sodium ◽  
Intestinal Inflammation ◽  
Therapeutic Potential ◽  
Activity Index ◽  
Critical Role ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Tanshinone Iia

Neutrophils play a critical role in the initiation and maintenance of intestinal inflammation. However, conventional neutrophil-targeted therapies can impair normal host defense. Tanshinone IIA has been recently revealed to act directly on neutrophils. Hence, we aimed at investigating whether Tanshinone IIA can protect against experimental colitis through modulation of neutrophils. We induced colitis in C57BL/6 mice by giving 3% dextran sulfate sodium (DSS) orally, and meanwhile, we treated mice daily with Tanshinone IIA intraperitoneally. The severity of colitis was evaluated by calculating disease activity index (DAI) and histological parameters. Neutrophil infiltration and activation in the colons of mice were measured. Moreover, whether Tanshinone IIA has direct effects on neutrophil migration and activation was determined in vitro. Our data showed that Tanshinone IIA significantly ameliorated the severity of DSS-induced colitis in mice, evidenced by the reduced DAI and improved colonic inflammation. In addition, Tanshinone IIA decreased neutrophil infiltration of intestinal mucosa and activation and reduced colonic inflammatory cytokines in DSS-treated mice. Furthermore, Tanshinone IIA was demonstrated to significantly suppress neutrophil migration and activation. These results provide compelling evidence that Tanshinone IIA has a therapeutic potential for alleviating inflammatory colitis in mice, which is possibly mediated by the immunomodulation of neutrophils.

scholarly journals Effects of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 2188-2195
Author(s):  
RC Woodman ◽  
PH Reinhardt ◽  
S Kanwar ◽  
FL Johnston ◽  
P Kubes
Keyword(s):  
Neutrophil Elastase ◽  
Human Neutrophil ◽  
Neutrophil Migration ◽  
Specific Inhibitor ◽  
Neutrophil Infiltration ◽  
Cathepsin G ◽  
Neutrophil Adhesion ◽  
Human Neutrophil Elastase

The primary objective of this study was to test the hypothesis that human neutrophil elastase (HNE) affects neutrophil infiltration (adhesion and emigration) into inflamed vessels. To determine whether HNE contributes to neutrophil adhesion in vivo, intravital microscopy was used to study neutrophil-endothelial cell interactions in single inflamed postcapillary venules. Superfusion of platelet-activating factor (PAF) (100 nmol/L) onto the mesentery caused an increase in neutrophil-neutrophil interactions, neutrophil adhesion to postcapillary venules, and cellular emigration out of the vasculature. Both L658 758 (an elastase-specific inhibitor), and Eglin C (an elastase and cathepsin G inhibitor) significantly attenuated all of these parameters in vivo. To further characterize the mechanism(s) involved, various in vitro parameters were assessed. HNE, but not trypsin, caused a dose-dependent (0.01 to 1.0 microgram/mL) increase in the expression of the beta subunit (CD18) of the CD11/CD18 adhesive glycoprotein complex on neutrophils. An HNE-dependent increase in CD11b expression was also observed; however, HNE did not affect the expression of other neutrophil adhesion molecules (L-selectin), superoxide production, or degranulation. PAF-enhanced CD18 expression on neutrophils and neutrophil migration were both abolished by L658 758 but PAF-induced neutrophil adhesion to endothelial monolayers was not affected by the antiproteinase. The in vitro data suggest that the antiproteinases do not directly prevent neutrophil adhesion in vivo but may be important in other CD18-dependent events such as neutrophil- neutrophil interaction or neutrophil infiltration (chemotaxis). These results translate into an important, rate-limiting role for elastase in the process of leukocyte infiltration and accumulation in inflamed microvessels.

scholarly journals Transporters MRP1 and MRP2 Regulate Opposing Inflammatory Signals To Control Transepithelial Neutrophil Migration duringStreptococcus pneumoniaeLung Infection

mSphere ◽  
2018 ◽  
Vol 3 (4) ◽  
Author(s):  
Andrew Zukauskas ◽  
Randall J. Mrsny ◽  
Paula Cortés Barrantes ◽  
Jerrold R. Turner ◽  
John M. Leong ◽  
...  
Keyword(s):  
Streptococcus Pneumoniae ◽  
Neutrophil Migration ◽  
Neutrophil Infiltration ◽  
Mortality Rates ◽  
Positive Bacterium ◽  
Immunomodulatory Agents ◽  
Content Type ◽  
Mouse Lungs

ABSTRACTStreptococcus pneumoniaeremains a source of morbidity and mortality in both developed and underdeveloped nations of the world. Disease can manifest as pneumonia, bacteremia, and meningitis, depending on the localization of infection. Interestingly, there is a correlation in experimental murine infections between the development of bacteremia and influx of neutrophils into the pulmonary lumen. Reduction of this neutrophil influx has been shown to improve survivability during infection. In this study, we usein vitrobiotinylation and neutrophil transmigration andin vivomurine infection to identify a system in which two epithelium-localized ATP-binding cassette transporters, MRP1 and MRP2, have inverse activities dictating neutrophil transmigration into the lumen of infected mouse lungs. MRP1 effluxes an anti-inflammatory molecule that maintains homeostasis in uninfected contexts, thus reducing neutrophil infiltration. During inflammatory events, however, MRP1 decreases and MRP2 both increases and effluxes the proinflammatory eicosanoid hepoxilin A3. If we then decrease MRP2 activity during experimental murine infection withS. pneumoniae, we reduce both neutrophil infiltration and bacteremia, showing that MRP2 coordinates this activity in the lung. We conclude that MRP1 assists in depression of polymorphonuclear cell (PMN) migration by effluxing a molecule that inhibits the proinflammatory effects of MRP2 activity.IMPORTANCEStreptococcus pneumoniaeis a Gram-positive bacterium that normally inhabits the human nasopharynx asymptomatically. However, it is also a major cause of pneumonia, bacteremia, and meningitis. The transition from pneumonia to bacteremia is critical, as patients that develop septicemia have ~20% mortality rates. Previous studies have shown that while neutrophils, a major bacterium-induced leukocyte, aid inS. pneumoniaeelimination, they also contribute to pathology and may mediate the lung-to-blood passage of the bacteria. Herein, we show that epithelium-derived MRP1 and MRP2 efflux immunomodulatory agents that assist in controlling passage of neutrophils during infection and that limiting neutrophil infiltration produced less bacteremia and better survival during murine infection. The importance of our work is twofold: ours is the first to identify an MRP1/MRP2 axis of neutrophil control in the lung. The second is to provide possible therapeutic targets to reduce excess inflammation, thus reducing the chances of developing bacteremia during pneumococcal pneumonia.

scholarly journals Intravenous antagomiR-494 lessens brain-infiltrating neutrophils by increasing HDAC2-mediated repression of multiple MMPs in experimental stroke

2019 ◽  
Author(s):  
Fangfang Li ◽  
Haiping Zhao ◽  
Guangwen Li ◽  
Sijia Zhang ◽  
Rongliang Wang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Damage ◽  
Neutrophil Migration ◽  
Glucose Deprivation ◽  
Neutrophil Infiltration ◽  
Predictive Biomarker ◽  
Experimental Stroke ◽  
Mmp Genes

Abstract Background: Neutrophil infiltration and phenotypic transformation are believed to contribute to neuronal damage and clinical outcome in ischemic stroke. Emerging evidence suggests that HDAC2 is an epigenetic regulator of inflammatory cells. Here, we investigated whether miR-494 affects HDAC2-mediated neutrophil infiltration and phenotypic shift. Methods: The miR-494 levels in neutrophils from AIS patients were detected by real-time PCR. C57BL/6J mice were subjected to transient middle cerebral artery occlusion, and the N1/N2 neutrophil shift was examined. Cortical neurons were subjected to oxygen-glucose deprivation and stimulated with supernatant from differently treated neutrophils or were cocultured with neutrophils; neuronal injury was detected, and ChIP-Seq was performed to clarify which genes are the binding targets of HDAC2. Finally, a transwell assay was conducted to examine neutrophil migration. Results: Compared to the control subjects, AIS patients had increased neutrophil expression of miR-494, and in AIS patients, elevated miR-494 expression in neutrophils was a predictor of worse neurological outcomes. MiR-494 correlates with the upregulation of adhesion molecules in neutrophils of AIS patients. Systemically administered antagomiR-494 partly shifts neutrophils into the N2 phenotype in MCAO mice. AntagomiR-494-treated neutrophils exert a neuroprotective role in vitro. ChIP-seq revealed that HDAC2 targets multiple MMP genes in neutrophils of AIS patients. Further in vitro and in vivo experiments showed that antagomiR-494 repressed expression of MMP genes, including MMP7, MMP10, MMP13, and MMP16, to reduce the number of brain-infiltrating neutrophils by regulating HDAC2. Conclusion: MiR-494 may serve as an alternative predictive biomarker of the outcome of AIS patients, and antagomiR-494 treatment decreased the expression of multiple MMPs and the infiltration of neutrophils partly by targeting HDAC2.

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