The roles of neutrophils and NETosis in systemic lupus erythematosis and rheumatoid arthritis
Hitory of NET
In 2004, an additional antimicrobial process was described by a group in Berlin. Brinkmann and his colleagues reported that, upon activation by phorbol myristate acetate (PMA), lipopolysaccharide (LPS), interleukin 8 (IL-8) or Gram-positive and -negative bacteria, neutrophils release their chromatin into the extracellular space forming the so-called neutrophil extracellular traps (NETs) (Brinkmann et al. 2004)
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Brinkmann
Rols of neutrophils in the pathogenesis of autoimmune diseases
formation of neutrophil extracellular traps (NETs)
synthesis of proinflammatory cytokines
direct tissue damage
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Processes of targeting microorganisms
1. degranulation
2. phagocytosis and degradation (ROS)
3. microbial trapping (NET)
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Neutrophils in injury or infection
adhesion to the activated vascular endothelium (β2-integrins and kindlin‑3)
extravasation and migration towards inflammatory foci
destruction of foreign microorganisms
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Neutrophil extracellular traps (NETs)
NETs target many pathogens
containing chromatin associated with granule enzymes
NETs represents a novel form of neutrophil death (termed NETosis)
© 2015, American College of Rheumatology
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2016, Nature Reviews Nephrology 12
.
Degradation of NETs
DNase 1
macrophage
an endonuclease that cleaves chromatin within NETs
through an active endocytic process that leads to the lysosome-mediated degradation of these lattices
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Netosis
a distinct process of cell death
generation of NETs
an important step of the innate immune response
can be triggered by both infectious and sterile’ stimuli
contributes to the activation of the immune system during inflammation
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Systemic autoimmune diseases
. a multistep processes
. responses to antigens are fairly specific
. clearance of apoptotic material is an important source of externalized autoantigens
. nuclear material release from NETs are more immunogenic
than apoptotic material.
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2001, Nature Immunology2
Rheumatoid arthritis characterized by:
synovial inflammation and hyperplasia
cartilage and bone destruction
autoantibody production (including ACPAs)
systemic features, including cardiovascular and pulmonary disorders
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.founding ACPAs in a significant percentage
of patients
. enhanced immunogenicity with immune complexes
. Detecting enhanced NETosis in:
_ circulating and synovial-fluid neutrophils,
_synovial tissue,
_rheumatoid nodules,
_ skin of affected patients.
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systemic lupus erythematosus (SLE)
involves multiple organs and skin
have an increased response to type I interferons
display a distinct granulocyte population, called low-density granulocytes (LDGs)
LDGs have an enhanced capacity to form NETs
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© 2016 Macmillan Publishers Limite
defect in NET clearance in patient with SLE
1.complement activation within NETs or from oxidation of nucleic acids externalized by the NETs
2.inhibitors of DNase 1
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lupus nephritis
Autoantibodies in patients with SLE vs RA
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As NET and mitocondria promote inflammation in autoimmune diseases, so design novel therapeutic methods that target this pathway or design drugs that target NETosis and mitocondrial ROS will lead to improved treatment of these diseases without markedly decreasing host defence and without tissue damage
Conclusion
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Refrences
Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y et al (2004) Neutrophil extracellular traps kill bacteria. Science 303(5663):1532–1535.
Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nature Reviews Immunology. 2017.
Branzk N, Papayannopoulos V, editors. Molecular mechanisms regulating NETosis in infection and disease. Seminars in immunopathology; 2013: Springer
Gupta S, Kaplan MJ. The role of neutrophils and NETosis in autoimmune and renal diseases. Nature Reviews Nephrology. 2016;12(7):402-13.
Wright HL, Moots RJ, Edwards SW. The multifactorial role of neutrophils in rheumatoid arthritis. Nature Reviews Rheumatology. 2014;10(10):593-601.
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