Lupus: the Essential Role of Mitochondria

-From 2016, articles commented in the Journal and Focus will be posted here (selection by Prof. JH Saurat M.D.)

Lupus: the Essential Role of Mitochondria

Postby CFH » Thu Mar 17, 2016 3:26 pm

Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease.
Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ.
Nat Med. 2016 Feb;22(2):146-53. doi: 10.1038/nm.4027. Epub 2016 Jan 18.


I. INTRODUCTION
-Autoimmune diseases are reactions of the body’s immune system directed against oneself.

-This arises from a misrecognition of surface proteins (Antigens) as being foreign.
-This is often the case of proteins which are shielded from immune recognizing cells (for example when Antigens are enclosed in a cell)

-Indeed, this misrecognition becomes even more destructive when the immune system is over-activated – as shown here Mitochondria are culprits.


II. THE ROLE OF NEUTROPHILS, AND THE THREE WAYS THEY ACT

1. Neutrophils: “nice to meet you”
-Neutrophils can be seen as front line soldiers of the immune system:
-They are very powerful White Blood Cells (leucocytes) which act in three different ways:
-a-by releasing intracellular granules aimed at “enemies” (foreign bacteria…): direct killing
-b-by “eating up the foreign bodies” (phagocytosis) and digesting them.
-c-by casting a “net” to trap foreign bodies (Neutrophil Extracellular Bodies). These paralyze and partially destroy the trapped bodies and partially digests them. If not eaten up completely by macrophages, debris can remain and initiate immunological reactions (immune or autoimmune).
They arrive first but are less specific and target foreign bacteria, cancer cells…

2. What is the “NET” made of ?
-It is made from the DNA of the neutrophils (YES!)
-Upon activation DNA is unwinded mixed with histones, impregnated with antimicrobial agents* and expelled from the cell.
*=myeloperoxidase, neutrophil elastase, defensins

-However the mechanism of their production is largely unknown
-Full video on NET: http://youtu.be/TIFmtnSdolM


III. What we learnt in this study ?
-DNA fragments called Ribonucleoprotein immune complexes (RNP IC) (for example from phagocytized targets) stimulate neutrophils which induce mitochondria to migrate towards the cell surface.
-Inflammation is induced by extracellular release of oxidized mitochondrial DNA (when injected in mice it stimulates type I interferon (IFN) signaling (through a pathway dependent on the DNA sensor STING)


IV. The Key-Point
Reactive Oxidized Species (ROS) coming from Mitochondria play an essential role:
-Mitochondrial ROS are also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus.
-This was also observed in individuals with chronic granulomatous disease, who lack NADPH oxidase activity but still develop autoimmunity and IFN inflammation.
-Mice experience less disease severity when Mitochondrial ROS is inhibited (IFN inflammation).


V. Take home message: Mitochondria play a role in neutrophil activity:
-in healthy immunity by the generation of NETs
-in autoimmune diseases by generating pro-inflammatory oxidized mitochondrial DNA.



VI. In practice:
-NET generation by neutrophils is quite a recent discovery of the action of neutrophils (2004)
-NET is an elegant way of isolating autoimmune theories
-Applicable here to lupus, optimizing NET generation to reduce could lead to new targeted management strategies.

CFH
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NET characteristics: healthy vs SLE
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CFH
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