Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever

Selina K Jorch; Annika McNally; Philipp Berger; Jonas Wolf; Kim Kaiser; Andrian Chetrusca Covash; Stefanie Robeck; Isabell Pastau; Olesja Fehler; Saskia-L Jauch-Speer; Sven Hermann; Michael Schäfers; Hanne Van Gorp; Apurva Kanneganti; Joke Dehoorne; Filomeen Haerynck; Federica Penco; Marco Gattorno; Jae Jin Chae; Paul Kubes; Mohamed Lamkanfi; Andy Wullaert; Markus Sperandio; Thomas Vogl; Johannes Roth; Judith Austermann

doi:10.1016/j.jaci.2023.01.037

Complex regulation of alarmins S100A8/A9 and secretion via gasdermin D pores exacerbates autoinflammation in familial Mediterranean fever

J Allergy Clin Immunol. 2023 Jul;152(1):230-243. doi: 10.1016/j.jaci.2023.01.037. Epub 2023 Feb 22.

Authors

Selina K Jorch¹, Annika McNally², Philipp Berger², Jonas Wolf², Kim Kaiser², Andrian Chetrusca Covash³, Stefanie Robeck², Isabell Pastau², Olesja Fehler², Saskia-L Jauch-Speer², Sven Hermann⁴, Michael Schäfers⁴, Hanne Van Gorp⁵, Apurva Kanneganti⁵, Joke Dehoorne⁶, Filomeen Haerynck⁶, Federica Penco⁷, Marco Gattorno⁷, Jae Jin Chae⁸, Paul Kubes⁹, Mohamed Lamkanfi⁵, Andy Wullaert¹⁰, Markus Sperandio¹¹, Thomas Vogl¹², Johannes Roth¹³, Judith Austermann²

Affiliations

¹ Institute of Immunology, University of Münster, Münster, Germany; Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
² Institute of Immunology, University of Münster, Münster, Germany.
³ Institute of Molecular Medicine and Experimental Immunology, University of Bonn, Bonn, Germany.
⁴ European Institute for Molecular Imaging, University of Münster, Münster, Germany; Cells in Motion Interfaculty Centre (CiM), University of Münster, Münster, Germany.
⁵ VIB Center for Inflammation Research, Ghent, and the Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium.
⁶ Department of Internal Medicine and Pediatrics, Ghent University Hospital, Ghent, Belgium.
⁷ Center for Autoinflammatory Diseases and Immunodeficiencies, IRCCS "Giannina Gaslini," Genoa, Italy.
⁸ Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
⁹ Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta.
¹⁰ VIB Center for Inflammation Research, Ghent, and the Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium; Laboratory of Protein Chemistry, Proteomics and Epigenetic Signalling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.
¹¹ Ludwig Maximilians University Munich, Walter Brendel Center for Experimental Medicine, Munich, Germany.
¹² Institute of Immunology, University of Münster, Münster, Germany; Cells in Motion Interfaculty Centre (CiM), University of Münster, Münster, Germany.
¹³ Institute of Immunology, University of Münster, Münster, Germany; Cells in Motion Interfaculty Centre (CiM), University of Münster, Münster, Germany. Electronic address: rothj@uni-muenster.de.

PMID: 36822481
DOI: 10.1016/j.jaci.2023.01.037

Abstract

Background: Familial Mediterranean fever (FMF), caused by mutations in the pyrin-encoding MEFV gene, is characterized by uncontrolled caspase-1 activation and IL-1β secretion. A similar mechanism drives inflammation in cryopyrin-associated periodic fever syndrome (CAPS) caused by mutations in NLRP3. CAPS and FMF, however, result in largely different clinical manifestations, pointing to additional, autoinflammatory pathways involved in FMF. Another hallmark of FMF is extraordinarily high expression of S100A8 and S100A9. These alarmins are ligands of Toll-like receptor 4 and amplifiers of inflammation. However, the relevance of this inflammatory pathway for the pathogenesis of FMF is unknown.

Objective: This study investigated whether mutations in pyrin result in specific secretion of S100A8/A9 alarmins through gasdermin D pores' amplifying FMF pathology.

Methods: S100A8/A9 levels in FMF patients were quantified by enzyme-linked immunosorbent assay. In vitro models with knockout cell lines and specific protein inhibitors were used to unravel the S100A8/A9 secretion mechanism. The impact of S100A8/A9 to the pathophysiology of FMF was analyzed with FMF (MEFV^V726A/V726A) and S100A9^-/- mouse models. Pyrin-S100A8/A9 interaction was investigated by coimmunoprecipitation, immunofluorescence, and enzyme-linked immunosorbent assay studies.

Results: The S100A8/A9 complexes directly interacted with pyrin. Knocking out pyrin, caspase-1, or gasdermin D inhibited the secretion of these S100 alarmins. Inflammatory S100A8/A9 dimers were inactivated by tetramer formation. Blocking this inactivation by targeted S100A9 deletion in a murine FMF model demonstrated the relevance of this novel autoinflammatory pathway in FMF.

Conclusion: This is the first proof that members of the S100 alarmin family are released in a pyrin/caspase-1/gasdermin D-dependent pathway and directly drive autoinflammation in vivo.

Keywords: FMF; MRP8/14 alternative secretion; S100A8/A9; autoinflammation; calprotectin; caspase-1; gasdermin D; myeloid related proteins; pyrin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alarmins
Animals
Calgranulin A / genetics
Caspases / metabolism
Cryopyrin-Associated Periodic Syndromes* / genetics
Familial Mediterranean Fever* / genetics
Gasdermins
Inflammation
Mice
Pyrin / genetics

Substances

Alarmins
Calgranulin A
Caspases
Gasdermins
Pyrin
S100a8 protein, mouse
S100A9 protein, mouse