Neutrophil extracellular traps in systemic autoimmune and autoinflammatory diseases

Abstract

Systemic autoimmune diseases are characterized by the failure of the immune system to differentiate self from non-self. These conditions are associated with significant morbidity and mortality, and they can affect many organs and systems, having significant clinical heterogeneity. Recent discoveries have highlighted that neutrophils, and in particular the neutrophil extracellular traps that they can release upon activation, can have central roles in the initiation and perpetuation of systemic autoimmune disorders and orchestrate complex inflammatory responses that lead to organ damage. Dysregulation of neutrophil cell death can lead to the modification of autoantigens and their presentation to the adaptive immune system. Furthermore, subsets of neutrophils that seem to be more prevalent in patients with systemic autoimmune disorders can promote vascular damage and increased oxidative stress. With the emergence of new technologies allowing for improved assessments of neutrophils, the complexity of neutrophil biology and its dysregulation is now starting to be understood. In this Review, we provide an overview of the roles of neutrophils in systemic autoimmune and autoinflammatory diseases and address putative therapeutic targets that may be explored based on this new knowledge.

Increased blood neutrophil extracellular traps (NETs) associated with early life stress: translational findings in recent-onset schizophrenia and rodent model

“…The release of NETs from neutrophils is crucial to immune defence and autoimmunity. However, exacerbated NETs foster chronic inflammation and controlling NETs has become a relevant therapeutical target for various non-infectious and autoimmune diseases [ 27 , 32 ].…”

“…These results extend previous findings of elevated neutrophils in schizophrenia [ 15 – 20 ], by mechanistically showing that these cells are in an active inflammatory state. It is becoming increasingly apparent that the release of NETs from neutrophils upon activation has a central role in both the initiation and chronicity of autoimmune and inflammatory diseases [ 32 ]. Some of the NETs-associated diseases, such as psoriasis, diabetes, and cardio-metabolic disorders, are comorbidities for psychosis and schizophrenia that contribute to a substantial reduction in life expectancy [ 25 – 32 ].…”

“…It is becoming increasingly apparent that the release of NETs from neutrophils upon activation has a central role in both the initiation and chronicity of autoimmune and inflammatory diseases [ 32 ]. Some of the NETs-associated diseases, such as psoriasis, diabetes, and cardio-metabolic disorders, are comorbidities for psychosis and schizophrenia that contribute to a substantial reduction in life expectancy [ 25 – 32 ]. Therefore, targeting neutrophil function may help controlling immune dysfunction to improve quality of life and life expectancy in schizophrenia.…”

“…NETs have also been involved in brain disorders, including stroke, traumatic brain injury, multiple sclerosis, and Alzheimer’s disease [ 34 , 35 ]. Studies have been investigating anti-NETs compounds to treat or prevent clinical inflammatory diseases [ 27 , 29 , 32 , 36 , 37 ]. However, NETs have never been investigated in psychiatric disorders.…”

“…The process of NETs formation is called NETosis, and this process is involved in the killing of bacteria, fungi, parasites, and viruses [21][22][23][24]. Interestingly, however, NETs have been implicated in various non-infectious diseases such as rheumatoid arthritis, lupus, psoriasis, diabetes, and cardio-metabolic disorders [25][26][27][28][29][30][31][32], some of which are comorbidities for psychosis and schizophrenia [8,33]. NETs have also been involved in brain disorders, including stroke, traumatic brain injury, multiple sclerosis, and Alzheimer's disease [34,35].…”