Neutrophil extracellular traps and pulmonary fibrosis: an update

Ernst

2023

Cells

Background: A total of 262 million people worldwide suffer from asthma and 461000 people died from it in 2019. Asthma is a disease with different endotypes defined by the granulocytes found in the asthmatic lung. In allergic asthma, the eosinophilic endotype is present, driven by a TH2 response. A TH17 immune response leads to the neutrophil endotype. This often causes uncontrolled asthma and is triggered by pollutants, microbes, and oxidative stress. It has been described that a significant number of patients with eosinophilic asthma develop mixed granulocytic asthma over time. The severity of asthma in the mixed endotype is related to the proportion of neutrophils in the lungs. Purpose: In this report, we address the question of how a TH2 response interacts with IL-17A in allergic asthma. Methods: To this end, we used a mouse model to induce allergic asthma followed by an aerosol challenge with ovalbumin. To investigate the role of IL-17A, we administered IL-17A intranasally during the challenge phase. Results: IL-17A alone did not elicit an immune response, whereas in combination with allergic asthma, it resulted in a shift of the asthmatic endotype from eosinophilic to neutrophilic. TGFβ1 was increased in these lungs compared to asthmatic lungs without IL-17A, as was the expression of the IL-17A receptor subunits IL-17RA and IL-17RC. In cultures with human cells, we also found that IL-17A increased the expression of its receptors only in combination with IL-13. We also found this effect for IL-8, which attracts neutrophils in humans. Conclusions: The TH2 response increased the sensitivity to IL-17A in a mouse asthma model as well as in human cell lines.

Section: Discussionmentioning

confidence: 99%

Interaction of Interleukin-17A with a Th2 Response in a Mouse Model of Allergic Airway Inflammation

Ernst

2023

Cells

Section: Neutrophils and Nets In Chronic Lung Diseasementioning

confidence: 99%

“…Lung fibroblasts, which constitute the majority of the cellular constituents of the lung parenchyma, are the major effectors of pulmonary fibrosis ( 170 ). Several NET components have been associated with fibroblast activation ( 170 ). Myofibroblasts exposed to NETs display increased expression of connective tissue growth factors, collagen production, and proliferation/migration, with these effects being mitigated by DNase-1 treatment ( 171 ).…”

Section: Neutrophils and Nets In Chronic Lung Diseasementioning

confidence: 99%

Neutrophil extracellular traps and long COVID

Shafqat,

Omer,

Albalkhi

et al. 2023

Front. Immunol.

Post-acute COVID-19 sequelae, commonly known as long COVID, encompasses a range of systemic symptoms experienced by a significant number of COVID-19 survivors. The underlying pathophysiology of long COVID has become a topic of intense research discussion. While chronic inflammation in long COVID has received considerable attention, the role of neutrophils, which are the most abundant of all immune cells and primary responders to inflammation, has been unfortunately overlooked, perhaps due to their short lifespan. In this review, we discuss the emerging role of neutrophil extracellular traps (NETs) in the persistent inflammatory response observed in long COVID patients. We present early evidence linking the persistence of NETs to pulmonary fibrosis, cardiovascular abnormalities, and neurological dysfunction in long COVID. Several uncertainties require investigation in future studies. These include the mechanisms by which SARS-CoV-2 brings about sustained neutrophil activation phenotypes after infection resolution; whether the heterogeneity of neutrophils seen in acute SARS-CoV-2 infection persists into the chronic phase; whether the presence of autoantibodies in long COVID can induce NETs and protect them from degradation; whether NETs exert differential, organ-specific effects; specifically which NET components contribute to organ-specific pathologies, such as pulmonary fibrosis; and whether senescent cells can drive NET formation through their pro-inflammatory secretome in long COVID. Answering these questions may pave the way for the development of clinically applicable strategies targeting NETs, providing relief for this emerging health crisis.

Rare Dis Orphan Drugs J

“…There are forms and releases in a process known as NETosis, a unique type of cell death, after recognizing specific pathogens. NETs persistence is regulated by DNase I and DNase-like proteins, which are responsible for maintaining a balance between the formation and degradation of neutrophil extracellular traps [19,20] . Abnormal level of release NETs can be associated with the pathogenesis of different disorders, including lung injury [19,21] , nephritis [22] , cardiovascular disease [23] , autoimmune disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus, antiphospholipid syndrome [18,22] ), as well as lung, breast or pancreatic cancer progression [24,25] .…”

Section: Human Neutrophil Elastasementioning

confidence: 99%

Neutrophil serine proteases

Skoreński¹,

Torzyk²,

Sieńczyk³

2023

The identification and characterization of the four active neutrophil serine proteases (NSPs) have provided a better understanding of their roles in various physiological and pathological processes. The availability of appropriate tools such as substrates, inhibitors, and activity-based probes (ABPs) for studying their activity and functions in cells has become increasingly important. In this paper, the authors provide a comprehensive overview of the current state of knowledge on the tools available for studying NSPs. The substrates, inhibitors, and ABPs that have been developed to date are described, including their strengths and limitations. The authors also discuss the potential implications of these tools for future research on NSPs, including their potential use in the development of new therapeutics for various diseases. Overall, this paper highlights the importance of understanding the activity and functions of NSPs and provides valuable information on the tools available for studying these proteases.