Telomere dysfunction promotes small vessel vasculitis via the LL37-NETs-dependent mechanism

Area of Science:

• Immunology
• Rheumatology
• Molecular Biology

Background:

• Small vessel vasculitis (SVV) is linked to neutrophil extracellular traps (NETs) and cathelicidin LL37.
• Telomere dysfunction may induce LL37, potentially driving NETs formation in SVV.

Purpose of the Study:

• To investigate if telomere dysfunction in neutrophils promotes SVV via an LL37-NETs-dependent pathway.
• To evaluate the role of LL37 in NETs release in SVV.

Main Methods:

• Compared NETs release in mice with and without telomere dysfunction or DNA damage.
• Measured neutrophil telomere length, LL37 expression, and NETs formation in SVV patients and controls.
• Assessed co-expression of γH2AX, LL37, and NETs in SVV patients.
• Utilized an LL37 inhibitor to confirm its role in NETs release.

Main Results:

• Telomere dysfunction and DNA damage in mice led to increased NETs, associated with higher LL37 levels.
• SVV patients exhibited shortened neutrophil telomeres, elevated LL37, and increased NETs.
• LL37 inhibition effectively reduced NETs release from neutrophils.

Conclusions:

• Telomere dysfunction appears to promote SVV through an LL37-dependent NETs mechanism.
• Targeting the LL37-NETs pathway presents a potential novel therapeutic strategy for SVV.