Neutrophils are key mediators in crescentic glomerulonephritis and targets for new therapeutic approaches
Marilina Antonelou1, Rhys D R Evans1, Scott R Henderson1
1University College London, Department of Renal Medicine, Royal Free Hospital, London, UK.
Insights
Neutrophils and their release of neutrophil extracellular traps (NETs) play a key role in crescentic glomerulonephritis (CGN). Targeting neutrophil activation offers a potential new therapy for CGN, moving beyond traditional glucocorticoids.
Area of Science:
- Nephrology
- Immunology
- Pathology
Background:
- Crescentic glomerulonephritis (CGN) involves immune dysregulation and loss of self-tolerance.
- Neutrophils are implicated in CGN pathogenesis through reactive oxygen species, serine proteases, and NET formation.
- NETs can cause direct tissue damage and present autoantigens, perpetuating autoimmune responses.
Purpose of the Study:
- To review the role of neutrophils in CGN development.
- To discuss neutrophil degranulation and NETosis pathways.
- To explore novel therapeutic strategies targeting neutrophils in CGN.
Main Methods:
- Review of experimental data and existing literature on neutrophil function in CGN.
- Analysis of the mechanisms of neutrophil degranulation and NETosis.
- Evaluation of potential therapeutic targets within neutrophil pathways.
Main Results:
- Neutrophils contribute to CGN via NETs, which can act as autoantigens.
- Aberrant neutrophil activation and NETosis are common in CGN.
- Impaired NET degradation is observed in some CGN cases.
- Novel compounds can target neutrophil degranulation and NETosis.
Conclusions:
- Neutrophil-derived NETs are central to CGN pathogenesis.
- Targeting neutrophil degranulation and NETosis presents a promising therapeutic avenue for CGN.
- This approach may offer an alternative to glucocorticoids with potentially fewer adverse effects.
Abstract:
Crescentic glomerulonephritis (CGN) results from a diverse set of diseases associated with immune dysregulation and the breakdown of self-tolerance to a wide range of autoantigens, some known and some that remain unknown. Experimental data demonstrate that neutrophils have an important role in the pathogenesis of CGN. Upon activation, neutrophils generate reactive oxygen species, release serine proteases and form neutrophil extracellular traps (NETs), all of which can induce direct tissue damage. In addition, serine proteases such as myeloperoxidase and proteinase 3, presented on NETs, can be processed and recognized as autoantigens, leading to the generation and maintenance of autoimmune responses in susceptible individuals. The basis of the specificity of autoimmune responses in different patients to NET proteins is unclear, but relates at least in part to differences in human leucocyte antigen expression. Conditions associated with CGN are often characterized by aberrant neutrophil activation and NETosis and, in some, impaired NET degradation. Targeting neutrophil degranulation and NETosis is now possible using a variety of novel compounds and may provide a promising therapeutic alternative to glucocorticoid use, which has been a mainstay of management in CGN for decades and is associated with significant adverse effects. In this review, we discuss the evidence supporting the role of neutrophils in the development of CGN and the pathways identified in neutrophil degranulation and NETosis that may translate to novel therapeutic applications.
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