The PYRIN domain is required for TLR4-mediated inflammation by PYHIN family members
Andrea Iannucci,
Davide Lacarbonara,
Valeria Caneparo,
Federica Castiglioni,
Andrea Butticè,
Stefano Raviola,
Chiara Porta,
Riccardo Miggiano,
Ivan Zanoni,
Marisa Gariglio,
Marco De Andrea
Affiliations
Andrea Iannucci
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Division of Immunology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USA
Davide Lacarbonara
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy
Valeria Caneparo
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy
Federica Castiglioni
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy
Andrea Butticè
Department of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, Italy
Stefano Raviola
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy
Chiara Porta
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, Italy
Riccardo Miggiano
Department of Pharmaceutical Sciences, University of Eastern Piedmont, 28100 Novara, Italy
Ivan Zanoni
Division of Immunology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USA; Division of Gastroenterology, Harvard Medical School, and Boston Children’s Hospital, Boston, MA 02115, USA
Marisa Gariglio
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Translational Medicine, University of Eastern Piedmont, 28100 Novara, Italy
Marco De Andrea
CAAD - Center for Translational Research on Autoimmune and Allergic Disease, University of Eastern Piedmont, 28100 Novara, Italy; Department of Public Health and Pediatric Sciences, University of Turin, Medical School, 10126 Turin, Italy; Corresponding author
Summary: 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 IFI16PYD 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.
