Neutrophil extracellular traps: A novel target for the treatment of stroke

Zhao, Ziyuan; Pan, Zirong; Zhang, Sen; Ma, Guodong; Zhang, Wen; Song, Junke; Wang, Yuehua; Kong, Ling-Lei; Du, Guanhua

doi:10.1016/j.pharmthera.2022.108328

Cited by 26 publications

(14 citation statements)

References 212 publications

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“…The mechanisms of NETosis (the process of NETs extrusion) are still controversial and warrant further investigation. To date, three distinct mechanisms have been identified in NETosis, categorized as suicidal NETosis, vital NETosis, and mitochondrial NETosis [ 65 ]. Suicidal NETosis is dependent on NOX and culminates in neutrophil death [ 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, CCN1 may induce suicidal NETosis by activating the NOX/ROS signaling pathway. As a secreted protein, CCN1 initiates intracellular signaling pathways through interactions with cell membrane receptors, such as integrins [ 24 , 65 ]. Furthermore, it has been reported that CCN1 directly binds to Toll-like receptors to activate neutrophil mobilization [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

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Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion

Li,

Qian,

et al. 2024

Cell Commun Signal

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Background Diabetic retinopathy (DR) is a major cause of blindness and is characterized by dysfunction of the retinal microvasculature. Neutrophil stasis, resulting in retinal inflammation and the occlusion of retinal microvessels, is a key mechanism driving DR. These plugging neutrophils subsequently release neutrophil extracellular traps (NETs), which further disrupts the retinal vasculature. Nevertheless, the primary catalyst for NETs extrusion in the retinal microenvironment under diabetic conditions remains unidentified. In recent studies, cellular communication network factor 1 (CCN1) has emerged as a central molecule modulating inflammation in pathological settings. Additionally, our previous research has shed light on the pathogenic role of CCN1 in maintaining endothelial integrity. However, the precise role of CCN1 in microvascular occlusion and its potential interaction with neutrophils in diabetic retinopathy have not yet been investigated. Methods We first examined the circulating level of CCN1 and NETs in our study cohort and analyzed related clinical parameters. To further evaluate the effects of CCN1 in vivo, we used recombinant CCN1 protein and CCN1 overexpression for gain-of-function, and CCN1 knockdown for loss-of-function by intravitreal injection in diabetic mice. The underlying mechanisms were further validated on human and mouse primary neutrophils and dHL60 cells. Results We detected increases in CCN1 and neutrophil elastase in the plasma of DR patients and the retinas of diabetic mice. CCN1 gain-of-function in the retina resulted in neutrophil stasis, NETs extrusion, capillary degeneration, and retinal leakage. Pre-treatment with DNase I to reduce NETs effectively eliminated CCN1-induced retinal leakage. Notably, both CCN1 knockdown and DNase I treatment rescued the retinal leakage in the context of diabetes. In vitro, CCN1 promoted adherence, migration, and NETs extrusion of neutrophils. Conclusion In this study, we uncover that CCN1 contributed to retinal inflammation, vessel occlusion and leakage by recruiting neutrophils and triggering NETs extrusion under diabetic conditions. Notably, manipulating CCN1 was able to hold therapeutic promise for the treatment of diabetic retinopathy.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion

Li,

Qian,

et al. 2024

Cell Commun Signal

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“…While the role of neutrophils in healing has been debated—with high numbers often equated with detrimental inflammation 50 , 51 alternative perspectives suggest neutrophils go beyond their traditional bactericidal roles. 37 Previous studies have highlighted the importance of myeloid cells in adult neovascularization and angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing

Yang,

Xie,

Xia

et al. 2024

IJN

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Background Neutrophils rapidly accumulate in large numbers at sites of tissue damage, exhibiting not only their well-known bactericidal capabilities but also playing crucial roles in angiogenesis and tissue repair. While exosomes derived from human umbilical cord mesenchymal stem cells (HucMSC-Exo) have emerged as a promising therapeutic tool, their exact mechanisms of action remain partly elusive. We hypothesize that HucMSC-Exo treatment may modulate neutrophil phenotypes, thereby significantly influencing wound healing outcomes. Methods HucMSC-Exo were isolated via ultracentrifugation and subsequently administered through subcutaneous injection into full-thickness cutaneous wounds in mice. To determine the impact of host neutrophils on the healing effects of HucMSC-Exo in skin injuries, strategies including neutrophil depletion and adoptive transfer were employed. Flow cytometry was used to evaluate the proportion of N2 subtype neutrophils in both normal and diabetic wounds, and the effect of HucMSC-Exo on this proportion was assessed. Furthermore, the mitochondrial metabolic reprogramming driven by HucMSC-Exo during N2 polarization was investigated through JC1 staining, ATP quantification, fatty acid uptake assays, and assessment of FAO-related genes ( Cpt1b, Acadm, and Acadl ). Results Depleting host neutrophils strikingly dampened prohealing effect of HucMSC-Exo on skin injury, while adoptive transfer of bone marrow neutrophils rescued this process. During normal healing process, some neutrophils expressed N2 markers, in contrast, diabetic wounds exhibited a reduced expression of N2 markers. After treatment with HucMSC-Exo, most neutrophils increased the phosphorylation of STAT6, leading to mitochondrial metabolic reprogramming and thus acquired an N2 phenotype. These N2 neutrophils, polarized by HucMSC-Exo, boosted the release of proangiogenic factors, particularly BV8, a myeloid cell-derived proangiogenic factor, and induced angiogenesis thereby favoring tissue restoration. Conclusion This research uniquely demonstrates the identification of N2 neutrophils in skin injury and shows that HucMSC-Exo could skew neutrophils toward N2 phenotype, enhancing our insight into how cells react to HucMSC-Exo.

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“…The focus of stroke is not only involved in vascular destruction and repair, but also an environment in which brain microvessels are in an inflammatory storm. In a short period after the occurrence of stroke, it will lead to the accumulation of aerobic metabolites and the production of free radical oxygen, and peripheral immune cells will be recruited to the brain for the first time [ 96 ]. Based on such a phenomenon, Feng et al [ 97 ] reported a neutrophil membrane-encapsulated nanoconjugated enzyme, which was synthesized from ferricyanide and polyethylpyrrolidone using a solid phase reaction method into a nanobased enzyme with enzyme-like activity and a mesoporous structure (MPBzyme), and then coated MPBzyme with differentiated HL-60 cell membrane, resulting in the formation of a nanoconjugated enzyme with neutral cell membrane properties (MPBzyme@NCM) (Fig.…”

Section: Application Of Biomimetic Membrane Materials In Different Cn...mentioning

confidence: 99%

Application and advances of biomimetic membrane materials in central nervous system disorders

Liao,

Lu,

Wang

et al. 2024

J Nanobiotechnol

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Central nervous system (CNS) diseases encompass spinal cord injuries, brain tumors, neurodegenerative diseases, and ischemic strokes. Recently, there has been a growing global recognition of CNS disorders as a leading cause of disability and death in humans and the second most common cause of death worldwide. The global burdens and treatment challenges posed by CNS disorders are particularly significant in the context of a rapidly expanding global population and aging demographics. The blood-brain barrier (BBB) presents a challenge for effective drug delivery in CNS disorders, as conventional drugs often have limited penetration into the brain. Advances in biomimetic membrane nanomaterials technology have shown promise in enhancing drug delivery for various CNS disorders, leveraging properties such as natural biological surfaces, high biocompatibility and biosafety. This review discusses recent developments in biomimetic membrane materials, summarizes the types and preparation methods of these materials, analyzes their applications in treating CNS injuries, and provides insights into the future prospects and limitations of biomimetic membrane materials.

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Neutrophil extracellular traps: A novel target for the treatment of stroke

Cited by 26 publications

References 212 publications

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion

Cellular communication network factor 1 promotes retinal leakage in diabetic retinopathy via inducing neutrophil stasis and neutrophil extracellular traps extrusion

HucMSC-Exo Induced N2 Polarization of Neutrophils: Implications for Angiogenesis and Tissue Restoration in Wound Healing

Application and advances of biomimetic membrane materials in central nervous system disorders

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