RNase T2 restricts TLR13-mediated autoinflammation in vivo

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• RNA-sensing Toll-like receptors (TLRs) detect non-self RNA in endolysosomes.
• RNase T2 processes RNA for TLR7/TLR8 engagement but also restricts RNA recognition.
• RNase T2 deficiency leads to neuroinflammation, impaired hematopoiesis, and splenomegaly in patients and mice.

Purpose of the Study:

• To elucidate the mechanism by which RNase T2 deficiency causes in vivo inflammation.
• To identify the specific TLR involved in RNase T2-deficient inflammation.
• To investigate the role of RNase T2 in regulating TLR activation by endogenous ligands.

Main Methods:

• Analysis of RNase T2-deficient mice (Rnaset2-/-).
• Genetic ablation of TLR13 in Rnaset2-/- mice.
• Assessment of inflammatory phenotypes in wild-type, Rnaset2-/-, and double-knockout mice, including in germ-free conditions.

Main Results:

• The inflammatory phenotype in Rnaset2-/- mice was completely abolished in the absence of TLR13.
• This TLR13-driven inflammation was present even in germ-free Rnaset2-/- mice, indicating an endogenous ligand.
• These findings suggest RNase T2 normally restricts TLR13 activation by an unidentified endogenous RNA ligand.

Conclusions:

• Toll-like receptor 13 (TLR13) is implicated in the neuroinflammation observed in RNase T2 deficiency.
• RNase T2 plays a crucial role in preventing aberrant TLR13 activation by endogenous RNA.
• TLR13 functions as a potential self-sensor that is normally regulated by RNase T2.