scholarly journals Nanoparticle-induced neutrophil apoptosis increases survival in sepsis and alleviates neurological damage in stroke

2019 ◽  
Vol 5 (11) ◽  
pp. eaax7964 ◽  
Author(s):  
Can Yang Zhang ◽  
Xinyue Dong ◽  
Jin Gao ◽  
Wenjing Lin ◽  
Ze Liu ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Ischemia Reperfusion ◽  
Human Neutrophils ◽  
Immune Homeostasis ◽  
Neutrophil Apoptosis ◽  
Precise Control ◽  
Programed Cell Death

Human neutrophils are the most abundant circulating leukocytes and contribute to acute and chronic inflammatory disorders. Neutrophil apoptosis is programed cell death to maintain immune homeostasis, but inflammatory responses to infections or tissue injury disrupt neutrophil death program, leading to many diseases. Precise control of neutrophil apoptosis may resolve inflammation to return immune homeostasis. Here, we report a method in which doxorubicin (DOX)–conjugated protein nanoparticles (NPs) can in situ selectively target inflammatory neutrophils for intracellular delivery of DOX that induces neutrophil apoptosis. We showed that neutrophil uptake of NPs required their activation and was highly selective. DOX release was triggered by acidic environments in neutrophils, subsequently inhibiting neutrophil transmigration and inflammatory responses. In two disease models, DOX-conjugated NPs notably increased mouse survival in sepsis and prevented brain damage in cerebral ischemia/reperfusion, but the NPs did not suppress systemic immunity. Our studies offer a promising strategy to treat inflammatory diseases.

scholarly journals Regulation of Neutrophil Degranulation and Cytokine Secretion: A Novel Model Approach Based on Linear Fitting

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Isabelle Naegelen ◽  
Nicolas Beaume ◽  
Sébastien Plançon ◽  
Véronique Schenten ◽  
Eric J. Tschirhart ◽  
...  
Keyword(s):  
Time Series ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cytokine Secretion ◽  
Human Neutrophils ◽  
Cytokine Release ◽  
Linear Fitting ◽  
Proinflammatory Mediators ◽  
The Relationship ◽  
Model Approach

Neutrophils participate in the maintenance of host integrity by releasing various cytotoxic proteins during degranulation. Due to recent advances, a major role has been attributed to neutrophil-derived cytokine secretion in the initiation, exacerbation, and resolution of inflammatory responses. Because the release of neutrophil-derived products orchestrates the action of other immune cells at the infection site and, thus, can contribute to the development of chronic inflammatory diseases, we aimed to investigate in more detail the spatiotemporal regulation of neutrophil-mediated release mechanisms of proinflammatory mediators. Purified human neutrophils were stimulated for different time points with lipopolysaccharide. Cells and supernatants were analyzed by flow cytometry techniques and used to establish secretion profiles of granules and cytokines. To analyze the link between cytokine release and degranulation time series, we propose an original strategy based on linear fitting, which may be used as a guideline, to (i) define the relationship of granule proteins and cytokines secreted to the inflammatory site and (ii) investigate the spatial regulation of neutrophil cytokine release. The model approach presented here aims to predict the correlation between neutrophil-derived cytokine secretion and degranulation and may easily be extrapolated to investigate the relationship between other types of time series of functional processes.

scholarly journals Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

2019 ◽  
Author(s):  
A.Y. Hsu ◽  
D. Wang ◽  
S. Liu ◽  
J. Lu ◽  
R. Syahirah ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Systemic Inflammation ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Neutrophil Migration ◽  
Human Neutrophils ◽  
Neutrophil Chemotaxis ◽  
Cycle Progression

AbstractNeutrophil migration is essential for inflammatory responses to kill pathogens, however it also causes tissue injury. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA overexpression screen in zebrafish, and identified eight microRNAs as potent suppressors of neutrophil migration. Among those,miR-199decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils,miR-199alters the cell cycle-related pathways and directly suppressescyclin-dependent kinase 2(cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting CDK2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils. Chemotaxis of primary human neutrophils are also reduced by CDK2 inhibition. Furthermore,miR-199overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Together, our results reveal previously unknown functions ofmiR-199and CDK2 in regulating neutrophil migration and provide new directions in alleviating systemic inflammation.One Sentence SummarymiR-199directly suppressescdk2expression, neutrophil chemotaxis and systemic inflammation.

Inhibition of neutrophil apoptosis by acrolein: a mechanism of tobacco-related lung disease?

2001 ◽  
Vol 281 (3) ◽  
pp. L732-L739 ◽  
Author(s):  
Erik I. Finkelstein ◽  
Mirella Nardini ◽  
Albert van der Vliet
Keyword(s):  
P38 Mapk ◽  
Inflammatory Diseases ◽  
Neutrophil Function ◽  
Human Neutrophils ◽  
Neutrophil Apoptosis ◽  
Membrane Asymmetry ◽  
Extracellular Signal ◽  
Dependent Inhibition ◽  
Mitogen Activated Protein ◽  
Inflammatory Processes

Cigarette smoking is known to contribute to inflammatory diseases of the respiratory tract by promoting recruitment of inflammatory-immune cells such as neutrophils and perhaps by altering neutrophil functional properties. We investigated whether acrolein, a toxic unsaturated aldehyde found in cigarette smoke, could directly affect neutrophil function. Exposure of freshly isolated human neutrophils to acrolein markedly inhibited spontaneous neutrophil apoptosis as indicated by loss of membrane asymmetry and DNA fragmentation and induced increased neutrophil production of the chemokine interleukin-8 (IL-8). Acrolein (1–50 μM) was found to induce marked activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinases (MAPKs), and inhibition of p38 MAPK activation by SB-203580 prevented acrolein-induced IL-8 release. However, inhibition of either ERK or p38 MAPK did not affect acrolein-dependent inhibition of apoptosis. Acrolein exposure prevented the activation of caspase-3, a crucial step in the execution of neutrophil apoptosis, presumably by direct inhibition of the enzyme. Our results indicate that acrolein may contribute to smoke-induced inflammatory processes in the lung by increasing neutrophil recruitment and reducing neutrophil clearance by apoptosis.

scholarly journals POS0376 MONOMERIC C REACTIVE PROTEIN (mCRP) REGULATES INFLAMMATORY RESPONSES IN HUMAN AND MOUSE CHONDROCYTES

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 418.2-418
Author(s):  
C. Ruiz-Fernández ◽  
M. González-Rodríguez ◽  
V. Francisco ◽  
I. M. Rajab ◽  
R. Gómez Bahamonde ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Intracellular Signaling ◽  
Inflammatory Responses ◽  
Proteolytic Enzymes ◽  
Inflammatory Diseases ◽  
Osteoclast Differentiation ◽  
Human Neutrophils ◽  
C Reactive Protein ◽  
Reactive Protein

Background:C-reactive protein (CRP) is an acute-phase protein that is used as an established biomarker to follow disease severity and progression in a plethora of inflammatory diseases. However, its pathophysiologic mechanisms of action are still poorly defined and remain elusive. CRP, in its pentameric form, exhibits weak anti-inflammatory activity. On the contrary, the monomeric isoform (mCRP) exhibits potent pro-inflammatory properties in endothelial cells, leukocytes, and platelets. So far, no data exists regarding mCRP effects in human or mouse chondrocytesObjectives:This work aimed to verify the pathophysiological relevance of mCRP in the etiology and/or progression of osteoarthritis (OA)Methods:We investigated the effects of mCRP in cultured human primary chondrocytes and in the chondrogenic ATDC5 mouse cell line. We determined mRNA and protein levels of relevant factors involved in inflammatory responses and the modulation of nitric oxide synthase type II (NOS2), an early inflammatory molecular target.Results:We demonstrate, for the first time, that monomeric C reactive protein increases NOS2, COX2, MMP13, VCAM1, IL-6, IL-8, and LCN2 expression in human and murine chondrocytes. We also demonstrated that NF-kB is a key factor in the intracellular signaling of mCRP-driven induction of pro-inflammatory and catabolic mediators in chondrocytes.Conclusion:mCRP exerts a sustained catabolic effect on human and murine chondrocytes, increasing the expression of inflammatory mediators and proteolytic enzymes, which can promote extracellular matrix (ECM) breakdown in healthy and OA cartilage. In addition, our results implicate the NF-kB signaling pathway in catabolic effects mediated by mCRP.References:[1]Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol. 2018;9(APR). doi:10.3389/fimmu.2018.00754[2]Francisco V, Pérez T, Pino J, et al. Biomechanics, obesity, and osteoarthritis. The role of adipokines: When the levee breaks. J Orthop Res. 2018;36(2):594-604. doi:10.1002/jor.23788[3]Kozijn AE, Tartjiono MT, Ravipati S, et al. Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet. Osteoarthr Cartil. 2019;27(1):118-128. doi:10.1016/j.joca.2018.09.007[4]Rajab IM, Majerczyk D, Olson ME, et al. C-reactive protein in gallbladder diseases: diagnostic and therapeutic insights. Biophys Reports. 2020;6(2-3):49-67. doi:10.1007/s41048-020-00108-9[5]Wu Y, Potempa LA, El Kebir D, Filep JG. C-reactive protein and inflammation: conformational changes affect function. Biol Chem. 2015;396(11):1181-1197. doi:10.1515/hsz-2015-0149[6]Thiele JR, Zeller J, Bannasch H, Stark GB, Peter K, Eisenhardt SU. Targeting C-Reactive Protein in Inflammatory Disease by Preventing Conformational Changes. Mediators Inflamm. 2015;2015(372432):9. doi:10.1155/2015/372432[7]Khreiss T, József L, Hossain S, Chan JSD, Potempa LA, Filep JG. Loss of pentameric symmetry of C-reactive protein is associated with delayed apoptosis of human neutrophils. J Biol Chem. 2002;277(43):40775-40781. doi:10.1074/jbc.M205378200[8]Jia ZK, Li HY, Liang YL, Potempa LA, Ji SR, Wu Y. Monomeric C-reactive protein binds and neutralizes receptor activator of NF-κB ligand-induced osteoclast differentiation. Front Immunol. 2018;9(FEB). doi:10.3389/fimmu.2018.00234[9]Francisco V, Ruiz-Fernández C, Pino J, et al. Adipokines: Linking metabolic syndrome, the immune system, and arthritic diseases. Biochem Pharmacol. 2019;165:196-206. doi:10.1016/j.bcp.2019.03.030[10]Ullah N, Ma FR, Han J, et al. Monomeric C-reactive protein regulates fibronectin mediated monocyte adhesion. Mol Immunol. 2020;117:122-130. doi:10.1016/j.molimm.2019.10.013[11]Boras E, Slevin M, Alexander MY, et al. Monomeric C-reactive protein and Notch-3 co-operatively increase angiogenesis through PI3K signalling pathway. Cytokine. 2014;69(2):165-179. doi:10.1016/j.cyto.2014.05.027Disclosure of Interests:None declared

scholarly journals Anti-Inflammatory Mechanisms of Fucoidans to Treat Inflammatory Diseases: A Review

Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 678
Author(s):  
Kalu K. Asanka Sanjeewa ◽  
Kalahe H. I. N. M. Herath ◽  
Hye-Won Yang ◽  
Cheol Soo Choi ◽  
You-Jin Jeon
Keyword(s):  
Marine Invertebrates ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Tumor Development ◽  
Functional Material ◽  
Brown Seaweeds ◽  
Anticancer Properties ◽  
Anti Inflammatory ◽  
Host Tissues

Fucoidans are sulfated heteropolysaccharides found in the cell walls of brown seaweeds (Phaeophyceae) and in some marine invertebrates. Generally, fucoidans are composed of significant amounts of L-fucose and sulfate groups, and lesser amounts of arabinose, galactose, glucose, glucuronic acid, mannose, rhamnose, and xylose. In recent years, fucoidans isolated from brown seaweeds have gained considerable attention owing to their promising bioactive properties such as antioxidant, immunomodulatory, anti-inflammatory, antiobesity, antidiabetic, and anticancer properties. Inflammation is a complex immune response that protects the organs from infection and tissue injury. While controlled inflammatory responses are beneficial to the host, leading to the removal of immunostimulants from the host tissues and restoration of structural and physiological functions in the host tissues, chronic inflammatory responses are often associated with the pathogenesis of tumor development, arthritis, cardiovascular diseases, diabetes, obesity, and neurodegenerative diseases. In this review, the authors mainly discuss the studies since 2016 that have reported anti-inflammatory properties of fucoidans isolated from various brown seaweeds, and their potential as a novel functional material for the treatment of inflammatory diseases.

scholarly journals Prolyl-Isomerase Pin1 Controls Key fMLP-Induced Neutrophil Functions

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1130
Author(s):  
Samia Bedouhene ◽  
Min Liu ◽  
Nassima Senani ◽  
Tarek Boussetta ◽  
Coralie Pintard ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Tissue Injury ◽  
Neutrophil Activation ◽  
Human Neutrophils ◽  
Prolyl Isomerase ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Gpcr Activation ◽  
Pharmacological Targets ◽  
Neutrophil Gelatinase ◽  
G Protein Coupled

Neutrophils are key cells of the innate immune and inflammatory responses. They are the first blood cells to migrate to the infection site where they release high amounts of reactive oxygen species (ROS) and several peptides and enzymes required for microbial killing. However, excessive neutrophil activation can induce tissue injury participating in inflammation, thus the characterization of the enzymes involved in neutrophil activation could help to identify new pharmacological targets to treat inflammation. The prolyl-isomerase Pin1 is a ubiquitous enzyme involved in several functions, however, its role in neutrophil functions is less known. In this study, we show that the bacterial peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP or fMLF), a G-protein coupled receptor (GPCR) agonist-induced Pin1 activation in human neutrophils. PiB and juglone, two Pin1 inhibitors inhibited Pin1 activity in neutrophils and consequently inhibited fMLP-induced chemotaxis and -degranulation of azurophil and specific granules as measured by myeloperoxidase and neutrophil gelatinase-associated lipocalin (NGAL) release respectively. We also showed that PiB inhibited TNFα + fMLP-induced superoxide production, confirming the effect of juglone. These data show that inhibitors of Pin1 impaired key pro-inflammatory neutrophil functions elicited by GPCR activation and suggest that Pin1 could control neutrophil inflammatory functions.

scholarly journals Cell-extrinsic autophagy in mature adipocytes regulates anti-inflammatory response to intestinal tissue injury through lipid mobilization

2021 ◽  
Author(s):  
Felix Clemens Richter ◽  
Matthias Friedrich ◽  
Mathilde Pohin ◽  
Ghada Alsaleh ◽  
Irina Guschina ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Intestinal Inflammation ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Protective Effects ◽  
Adipose Tissue Macrophages ◽  
Anti Inflammatory ◽  
Major Nutrients

Autophagy is a critical cellular recycling pathway which is genetically linked to the development of intestinal inflammation in humans. Inflammation drives adipose tissue breakdown and provision of major nutrients such as free fatty acids (FFA). However, the effect of autophagy-mediated FFA release by adipocytes in immune-mediated inflammatory diseases remains unexplored. In a mouse model of intestinal inflammation, we found that visceral adipocytes upregulate autophagy at peak inflammation. Adipocyte-specific loss of the key autophagy gene Atg7 (Atg7Ad) resulted in the exacerbation of intestinal inflammation. TNFα-induced lipolysis was impaired in Atg7-deficient adipocytes leading to the reduced availability of several FFA species, and decreased expression of the FFA transporter CD36 on adipose tissue macrophages (ATMs). Visceral adipose tissues from Atg7Ad mice released less IL-10 resulting in lower levels of circulating IL-10 in colitis. ATMs present the main source of adipose tissue-derived IL-10 during colitis. In vitro assays confirmed that FFA restriction from macrophages reduced CD36 expression and diminished IL-10 production. Taken together, our study demonstrates that autophagy-mediated FFA release from adipocytes directs anti-inflammatory responses in ATMs, which in turn conveys protective effects for distant intestinal inflammation.

ST266 Improves Oxygenation and Reduces Tissue Injury in an In-Situ Rat Left Lung Ischemia-Reperfusion Model

2017 ◽  
Vol 36 (4) ◽  
pp. S375
Author(s):  
C.F. Evans ◽  
X. Wang ◽  
X. Liu ◽  
R. Mishra ◽  
V. Mishra ◽  
...  
Keyword(s):  
Tissue Injury ◽  
Ischemia Reperfusion ◽  
Left Lung

scholarly journals Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration

2019 ◽  
Vol 116 (37) ◽  
pp. 18561-18570 ◽  
Author(s):  
Alan Y. Hsu ◽  
Decheng Wang ◽  
Sheng Liu ◽  
Justice Lu ◽  
Ramizah Syahirah ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Systemic Inflammation ◽  
Human Neutrophil ◽  
Cell Cycle Progression ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Neutrophil Migration ◽  
Formyl Peptide Receptor ◽  
Human Neutrophils ◽  
Formyl Peptide

Neutrophil migration is essential for inflammatory responses to kill pathogens; however, excessive neutrophilic inflammation also leads to tissue injury and adverse effects. To discover novel therapeutic targets that modulate neutrophil migration, we performed a neutrophil-specific microRNA (miRNA) overexpression screen in zebrafish and identified 8 miRNAs as potent suppressors of neutrophil migration. Among those,miR-199decreases neutrophil chemotaxis in zebrafish and human neutrophil-like cells. Intriguingly, in terminally differentiated neutrophils,miR-199alters the cell cycle-related pathways and directly suppresses cyclin-dependent kinase 2 (Cdk2), whose known activity is restricted to cell cycle progression and cell differentiation. Inhibiting Cdk2, but not DNA replication, disrupts cell polarity and chemotaxis of zebrafish neutrophils without inducing cell death. Human neutrophil-like cells deficient in CDK2 fail to polarize and display altered signaling downstream of the formyl peptide receptor. Chemotaxis of primary human neutrophils is also reduced upon CDK2 inhibition. Furthermore,miR-199overexpression or CDK2 inhibition significantly improves the outcome of lethal systemic inflammation challenges in zebrafish. Our results therefore reveal previously unknown functions ofmiR-199and CDK2 in regulating neutrophil migration and provide directions in alleviating systemic inflammation.

scholarly journals Monocyte Chemotactic Protein-Induced Protein 1 (MCPIP-1): A Key Player of Host Defense and Immune Regulation

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhuqing Jin ◽  
En Zheng ◽  
Candice Sareli ◽  
Pappachan E. Kolattukudy ◽  
Jianli Niu
Keyword(s):  
Inflammatory Response ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Inflammatory Diseases ◽  
Current Evidence ◽  
Protective Mechanism ◽  
Immune Functions ◽  
Resolution Of Inflammation ◽  
Knock Out ◽  
The Stability

Inflammatory response is a host-protective mechanism against tissue injury or infections, but also has the potential to cause extensive immunopathology and tissue damage, as seen in many diseases, such as cardiovascular diseases, neurodegenerative diseases, metabolic syndrome and many other infectious diseases with public health concerns, such as Coronavirus Disease 2019 (COVID-19), if failure to resolve in a timely manner. Recent studies have uncovered a superfamily of endogenous chemical molecules that tend to resolve inflammatory responses and re-establish homeostasis without causing excessive damage to healthy cells and tissues. Among these, the monocyte chemoattractant protein-induced protein (MCPIP) family consisting of four members (MCPIP-1, -2, -3, and -4) has emerged as a group of evolutionarily conserved molecules participating in the resolution of inflammation. The focus of this review highlights the biological functions of MCPIP-1 (also known as Regnase-1), the best-studied member of this family, in the resolution of inflammatory response. As outlined in this review, MCPIP-1 acts on specific signaling pathways, in particular NFκB, to blunt production of inflammatory mediators, while also acts as an endonuclease controlling the stability of mRNA and microRNA (miRNA), leading to the resolution of inflammation, clearance of virus and dead cells, and promotion of tissue regeneration via its pleiotropic effects. Evidence from transgenic and knock-out mouse models revealed an involvement of MCPIP-1 expression in immune functions and in the physiology of the cardiovascular system, indicating that MCPIP-1 is a key endogenous molecule that governs normal resolution of acute inflammation and infection. In this review, we also discuss the current evidence underlying the roles of other members of the MCPIP family in the regulation of inflammatory processes. Further understanding of the proteins from this family will provide new insights into the identification of novel targets for both host effectors and microbial factors and will lead to new therapeutic treatments for infections and other inflammatory diseases.

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