The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members.

Innate immunity relies on pattern recognition receptors (PRRs) to detect threats, including pathogens and damage-associated molecular patterns (DAMPs) from damaged cells. IFI16 behaves as a DAMP and activates Toll-like receptor 4 (TLR4)-mediated inflammation. Here, we identify the N-terminal PYRIN domain (PYD) of IFI16 as critical for binding TLR4 and triggering inflammation, and we confirm this interaction through in vitro and in vivo assays. The inflammatory activity of IFI16(PYD) is unique to human and mouse PYHIN proteins, as PYDs in other proteins, such as NLRP3 or ASC, do not activate TLR4. Disrupting the IFI16-TLR4 interaction prevents pro-inflammatory cytokine production, reducing immune cell recruitment and skin fibrosis in mice. Elevated IFI16 and TLR4 levels in systemic sclerosis patients suggest a role in disease progression. These findings provide insight into DAMP recognition and inflammation propagation, highlighting the IFI16-TLR4 interaction as a potential therapeutic target for sterile inflammatory diseases.