Heterogeneity of neutrophils in arterial hypertension

Significance 

Neutrophils are a type of innate immune cell that contains distinctive cytoplasmic granules and a nucleus that is divided into three segments. They are the most abundant immune cell type in the blood. Neutrophil blood levels increase naturally in response to infections, injuries, and other types of stress. Neutrophils are rapidly recruited to infected tissues and can engulf bacteria directly or produce toxic antimicrobial mediators.

Receptors expressed on neutrophils membrane surface along with neutrophils transcriptional activity are expected to affect the functional features of neutrophils. This is why there exist various neutrophils subsets in circulation. These neutrophil subsets have specific functions, and their distribution in circulation depends on pathological and hemostatic conditions. Density gradient separation of blood can help identify two forms of neutrophils: low-density neutrophils and normal-density neutrophils. Low-density neutrophils are associated with specific autoimmune ailments and inflammation, and immunosuppression is often linked to neutrophil diversity.

Low-density neutrophils are thought to be prematurely released unformed neutrophils, but research shows that they could also be degranulated neutrophils that have decreased density. Autoimmune disease studies on ailments such as rheumatoid arthritis, psoriasis, and lupus erythematosus, give a deeper understating of neutrophil heterogeneity in inflammation.

Arterial hypertension is a cardiovascular condition and one of the world’s leading causes of death. The origin of this pathophysiology is complex and multifactorial, and it involves the interaction of several physiological systems boosted by exposure to environmental risk factors. Recently, new mechanisms associated with the onset of hypertension and its progression to cardiovascular disease have been discussed, where the immune system and its activation may be critical indicating a connection between chronic inflammation and hypertension pathophysiology

Previously, researchers at Instituto Politécnico Nacional in Mexico, Professor Doris Cerecedo, Dr. Ivette Martínez-Vieyra, Edgar Oliver Lopez-Villegas, Professor Arturo Hernandez-Cruz, and Arlet del Carmen Loza-Huerta, showed that plenty of neutrophils in hypertension patients are activated. They also demonstrated that neutrophils in these patients express high endothelial sodium channel levels, and their circulating proportions are more diverse than in healthy individuals. In a new follow up   study, the authors sought to investigate whether specific neutrophil species contribute to hypertension-related inflammation and whether hypertension neutrophils show diverse sodium influx levels. The original research article is now published in the journal Experimental Cell Research.

The research team isolated both normal-density and low-density neutrophil subpopulations from hypertension patients and healthy individuals. Through flow cytometric investigation, the authors determined sodium flux and compared reactive oxygen species, expression of maturity markers CD66b, CD63, CD16, CD11b, and CD15, and neutrophil extracellular traps influence in apoptosis in low- and normal-density neutrophil subpopulations from hypertension patients and healthy individuals.

The findings showed that hypertension patients’ normal-density and low-density neutrophils have high sodium influx levels and features of activation. They also exhibited high endothelial sodium channel levels; therefore, they could introduce more sodium ions than neutrophils from healthy individuals. These results show that both normal-density and low-density neutrophils from hypertension patients are always activated, which secrete their granule contents resulting in an inadequate response to harmful substances.

Normal density neutrophils from healthy individuals recorded higher expression levels of maturity marker CD16 than those from hypertension patients. Low-density neutrophils from hypertension patients expressed higher activation markers levels and were observed to circulate in a more activated form than in healthy individuals. Therefore, low-density subpopulations from hypertension patients are more likely to cause and amplify inflammation.

Although reactive oxygen species produced in mitochondria are linked to hypertension, their actions remain unclear. Therefore, neutrophils from hypertension patients should have recorded higher reactive oxygen species levels. However, low reactive oxygen species levels were recorded for normal-density neutrophils from hypertension patients, suggesting that these cells couldn’t generate mitochondrial reactive oxygen species since the mitochondria had lost their functionality. Electron microscopy analysis of damaged mitochondria in neutrophils of hypertension patients validated this phenomenon.

Altered mitochondria should have enhanced apoptosis; contrarily, normal-density neutrophils from hypertension patients recorded low apoptosis levels. Low-density neutrophils showed comparable apoptosis levels for both healthy individuals and hypertension patients. Moreover, low-density neutrophils from hypertension patients exhibited a lower capacity to form neutrophil extracellular traps, meaning that these cells were less competent. Immaturity or an adaptation to avoid tissue damage could be the reason behind this.

On the basis of the evidence shown in the paper by Professor Doris Cerecedo and colleagues, neutrophil function appears to go beyond its role in fighting pathogen infection. Indeed, neutrophils could participate in the arterial hypertension development favoring the generation of vascular dysfunction. The detailed characterization of neutrophils undertaken in the study will advance our understanding of the role of neutrophils in arterial hypertension.

neutrophils-medicine innovates
neutrophils-medicine innovates

Reference

Doris Cerecedo, Ivette Martínez-Vieyra, Edgar Oliver Lopez-Villegas, Arturo Hernández-Cruz, and Arlet del Carmen Loza-Huerta. Heterogeneity of neutrophils in arterial hypertension. Experimental Cell Research, issue 402 (2021), 112577.

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