Targeting Neutrophils for Promoting the Resolution of Inflammation

Filep, János G.

doi:10.3389/fimmu.2022.866747

Cited by 50 publications

(41 citation statements)

References 292 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…These inflammatory cells initially accumulate near the lesion to resolve the injury, and facilitate healing, which remarkably alters the cardiac microenvironment ( 1 , 3 , 5 – 7 , 26 ), thus providing a setting for the onset of fibrosis. In this respect, neutrophils represent the first cells recruited to the site of cardiac injury ( 3 , 5 , 6 , 26 , 29 , 30 ), in order to release granular content (e.g., myeloperoxidase, cathepsins, and neutrophil gelatinase associated lipocalin), as well as expressing its phagocytic nature, providing extracellular chromatin traps which have been enriched with inflammatory enzymes ( 5 ). In addition to being quintessential proinflammatory cells, substantial evidence indicates that neutrophils serve as introductory modulators of the cardiac healing and remodeling process ( 3 , 5 , 26 , 29 ), by means of phenotype shifting (N1 to N2) ( 30 ).…”

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

“…In this respect, neutrophils represent the first cells recruited to the site of cardiac injury ( 3 , 5 , 6 , 26 , 29 , 30 ), in order to release granular content (e.g., myeloperoxidase, cathepsins, and neutrophil gelatinase associated lipocalin), as well as expressing its phagocytic nature, providing extracellular chromatin traps which have been enriched with inflammatory enzymes ( 5 ). In addition to being quintessential proinflammatory cells, substantial evidence indicates that neutrophils serve as introductory modulators of the cardiac healing and remodeling process ( 3 , 5 , 26 , 29 ), by means of phenotype shifting (N1 to N2) ( 30 ). Accordingly, neutrophils generate several pro-fibrotic mediators, namely interleukin (IL)-1β, NADPH oxidase 4 (Nox4), and metalloproteinases (MMPs), that, in conjunction with large amounts of generated reactive oxygen species (ROS), induce cardiac fibroblasts transdifferentiation, via protein kinase B/mammalian target of rapamycin (Akt/mTOR) nuclear factor-κβ (NF-κβ) signaling ( 3 ).…”

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

“…The NLRP3 inflammasome relates to an intracellular pattern recognition receptor that responds to pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs), generating IL-1β and IL-18 and upregulating Smad 2/3 signaling, thus triggering cardiac inflammation, and fibrosis ( 6 , 9 , 28 ). In addition, it is likely that neutrophils obtain indirect pro-fibrotic properties by releasing extracellular traps (NETs) ( 3 , 5 , 6 , 30 ). The NET release (NETosis) represents a response to different stimuli, whereas neutrophil elastase, and myeloperoxidase translocate from cytosolic granules into the nucleus, breaking down chromatin and the nuclear envelope, followed by a release of neutrophil content ( 30 ).…”

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

“…In addition, it is likely that neutrophils obtain indirect pro-fibrotic properties by releasing extracellular traps (NETs) ( 3 , 5 , 6 , 30 ). The NET release (NETosis) represents a response to different stimuli, whereas neutrophil elastase, and myeloperoxidase translocate from cytosolic granules into the nucleus, breaking down chromatin and the nuclear envelope, followed by a release of neutrophil content ( 30 ). Activated NETosis likely induces platelet accumulation, and activation, as well as secretion of pro-fibrotic mediators, such as TGF-β and PGDF, whereas fibroblasts exposed to NETs achieve the competence to proliferate, transdifferentiate, and produce collagens ( 3 ).…”

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

“…Finally, neutrophils that undergo apoptosis generate anti-inflammatory signals (TGF-β, IL-10), aiming for a pro-resolving response ( 3 , 29 ). Although neutrophils have a short life-span, evidence indicates that they persist after cardiac injury, taking part in ECM reorganization, thus enhancing cardiac fibrosis ( 3 , 29 , 30 ). These traits, if poorly regulated, make neutrophils potentially insidious, so supervision of neutrophil-initiated inflammation may be particularly important for the alleviation of the cardiac fibroproliferation feedback ( 3 , 5 , 29 , 30 ).…”

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

See 4 more Smart Citations

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

Stojanović

Mitić

Stojanović

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Cardiac fibrosis represents a redundant accumulation of extracellular matrix proteins, resulting from a cascade of pathophysiological events involved in an ineffective healing response, that eventually leads to heart failure. The pathophysiology of cardiac fibrosis involves various cellular effectors (neutrophils, macrophages, cardiomyocytes, fibroblasts), up-regulation of profibrotic mediators (cytokines, chemokines, and growth factors), and processes where epithelial and endothelial cells undergo mesenchymal transition. Activated fibroblasts and myofibroblasts are the central cellular effectors in cardiac fibrosis, serving as the main source of matrix proteins. The most effective anti-fibrotic strategy will have to incorporate the specific targeting of the diverse cells, pathways, and their cross-talk in the pathogenesis of cardiac fibroproliferation. Additionally, renalase, a novel protein secreted by the kidneys, is identified. Evidence demonstrates its cytoprotective properties, establishing it as a survival element in various organ injuries (heart, kidney, liver, intestines), and as a significant anti-fibrotic factor, owing to its, in vitro and in vivo demonstrated pleiotropy to alleviate inflammation, oxidative stress, apoptosis, necrosis, and fibrotic responses. Effective anti-fibrotic therapy may seek to exploit renalase’s compound effects such as: lessening of the inflammatory cell infiltrate (neutrophils and macrophages), and macrophage polarization (M1 to M2), a decrease in the proinflammatory cytokines/chemokines/reactive species/growth factor release (TNF-α, IL-6, MCP-1, MIP-2, ROS, TGF-β1), an increase in anti-apoptotic factors (Bcl2), and prevention of caspase activation, inflammasome silencing, sirtuins (1 and 3) activation, and mitochondrial protection, suppression of epithelial to mesenchymal transition, a decrease in the pro-fibrotic markers expression (’α-SMA, collagen I, and III, TIMP-1, and fibronectin), and interference with MAPKs signaling network, most likely as a coordinator of pro-fibrotic signals. This review provides the scientific rationale for renalase’s scrutiny regarding cardiac fibrosis, and there is great anticipation that these newly identified pathways are set to progress one step further. Although substantial progress has been made, indicating renalase’s therapeutic promise, more profound experimental work is required to resolve the accurate underlying mechanisms of renalase, concerning cardiac fibrosis, before any potential translation to clinical investigation.

show abstract

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

Section: The Pathophysiology Of Cardiac Fibrosismentioning

confidence: 99%

See 3 more Smart Citations

The Scientific Rationale for the Introduction of Renalase in the Concept of Cardiac Fibrosis

Stojanović

Mitić

Stojanović

et al. 2022

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

show abstract

Effect of stretching on inflammation in a subcutaneous carrageenan mouse model analyzed at single‐cell resolution

Berrueta,

Muñoz‐Vergara,

Martin

et al. 2023

Journal Cellular Physiology

View full text Add to dashboard Cite

Understanding the factors that influence the biological response to inflammation is crucial, due to its involvement in physiological and pathological processes, including tissue repair/healing, cancer, infections, and autoimmune diseases. We have previously demonstrated that in vivo stretching can reduce inflammation and increase local pro‐resolving lipid mediators in rats, suggesting a direct mechanical effect on inflammation resolution. Here we aimed to explore further the effects of stretching at the cellular/molecular level in a mouse subcutaneous carrageenan‐inflammation model. Stretching for 10 min twice a day reduced inflammation, increased the production of pro‐resolving mediator pathway intermediate 17‐HDHA at 48 h postcarrageenan injection, and decreased both pro‐resolving and pro‐inflammatory mediators (e.g., PGE2 and PGD2) at 96 h. Single‐cell RNA sequencing analysis of inflammatory lesions at 96 h showed that stretching increased the expression of both pro‐inflammatory (Nos2) and pro‐resolution (Arg1) genes in M1 and M2 macrophages at 96 h. An intercellular communication analysis predicted specific ligand–receptor interactions orchestrated by neutrophils and M2a macrophages, suggesting a continuous neutrophil presence recruiting immune cells such as activated macrophages to contain the antigen while promoting resolution and preserving tissue homeostasis.

show abstract