C1q reprograms innate immune memory

Inge Jonkman¹Maaike Jacobs¹Yutaka Negishi^2,3Julia I P Van Heck⁴Vasiliki Matzaraki⁴Joost H A Martens²Marijke Baltissen²Michiel Vermeulen²Zahi A Fayad⁵Abraham J P Teunissen^5,6,7,8Willem J M Mulder^4,5,6,9Luuk Hilbrands¹Leo AB Joosten^10,4Mihai Netea^11,4Musa Mhlanga^2,3Nils Rother¹Raphaël Duivenvoorden^1,4,5*

• ¹Department of Nephrology, Radboud University Medical Centre, Nijmegen, Gelderland, Netherlands
• ²Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, Netherlands
• ³Department of Cell Biology, Faculty of Science, Radboud University, Nijmegen, Netherlands
• ⁴Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Gelderland, Netherlands
• ⁵BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁶Department of Diagnostic, Molecular and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁷Cardiovascular Research Institute, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁸Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, New York, United States
• ⁹Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands
• ¹⁰Department of Medical Genetics, University of Medicine and Pharmacy, Iuliu Haţieganu, Cluj-Napoca, Romania
• ¹¹Department of Immunology and Metabolism, Life and Medical Science Institute, Univeristy of Bonn, Bonn, Germany

Innate immune memory, also called trained immunity, is a metabolic and epigenetically regulated process that enables innate immune cells to recalibrate their inflammatory reactivity in response to pathogenic or endogenous stimuli. In addition to its function in host defense, trained immunity contributes to diverse immune-mediated diseases. We discovered that complement component 1q ( C1q) is an effective modulator of innate immune memory, potently suppressing the responsiveness of myeloid cells. We found that C1q leads to profound reprogramming of myeloid cell metabolism, particularly glycolysis, and exerts control over the transcriptional regulation of important metabolic and inflammatory genes. We corroborate our findings by identifying single-nucleotide polymorphisms close to the C1q gene that are linked to induction of trained immunity by Bacillus Calmete Guérin (BCG) or beta-glucan in healthy peripheral blood mononuclear cells (PBMCs). Our results reveal a immunomodulatory role for C1q and provide evidence of a molecular interaction between the complement system and innate immune memory. These findings expand our understanding of innate immune memory.