Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation

Cecilia Svanberg; Helena Enocsson; Melissa Govender; Klara Martinsson; Lawrence A Potempa; Ibraheem M Rajab; Rafael Fernandez-Botran; Jonas Wetterö; Marie Larsson; Christopher Sjöwall

doi:10.1016/j.jaut.2023.102998

Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation

J Autoimmun. 2023 Feb:135:102998. doi: 10.1016/j.jaut.2023.102998. Epub 2023 Jan 25.

Affiliations

¹ Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Linköping University, Linköping, Sweden.
² Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden.
³ Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States.
⁴ Department of Pathology & Laboratory Medicine, University of Louisville, Louisville, KY, United States.
⁵ Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden. Electronic address: christopher.sjowall@liu.se.

PMID: 36706536
DOI: 10.1016/j.jaut.2023.102998

Abstract

Presence of autoantibodies targeting nuclear constituents, i.e., double-stranded DNA and small nuclear ribonucleoproteins (snRNPs), remain a cornerstone in systemic lupus erythematosus (SLE). Fcγ receptor IIa (FcγRIIa) dependent uptake of nucleic acid containing immune complexes (ICs) by plasmacytoid dendritic cells (PDCs) can activate toll-like receptors (TLRs) such as TLR7 and TLR9 resulting in type I interferon (IFN) production. Previously, the classical liver-derived acute-phase reactant C-reactive protein (CRP) has been suggested to reduce IC-induced type I IFN production, whereas monomeric (mCRP) vs. pentameric (pCRP) mediated effects have not yet been unraveled. Herein, peripheral blood mononuclear cells (PBMCs) or enriched blood DCs from healthy volunteers were stimulated with SLE sera, snRNP-IgG (ICs), or TLR ligands with or without pCRP, mCRP, or anti-FcγRIIa antibody. Type I IFNs and cytokine responses were investigated using quantitative PCR, ELISA, and flow cytometry. pCRP inhibited IFN gene expression in PBMCs and enriched DCs after incubation with ICs, compared to ICs alone, whereas mCRP had significantly less inhibitory effect. The effect was independent on the order in which IC or CRP was added to the cells. In addition, pCRP inhibited IFN induced by other TLR stimulators, implicating broader inhibitory effects induced by pCRP. We demonstrate pronounced immunoregulatory functions of CRP whereas the inhibitory properties were evidently dependent on CRP's intact conformational state. The inhibition of type I IFNs was not due to competition of FcγRs, or binding of CRP to the ICs. Our findings have implications for autoimmune IC-mediated conditions imprinted by type I IFN gene dysregulation.

Keywords: C-reactive protein; Dendritic cells; Immune complex; Systemic lupus erythematosus; Type I interferons.

Publication types

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

MeSH terms

Antigen-Antibody Complex
C-Reactive Protein / metabolism
Dendritic Cells
Humans
Interferon Type I* / metabolism
Leukocytes, Mononuclear
Lupus Erythematosus, Systemic*

Substances

Interferon Type I
Antigen-Antibody Complex
C-Reactive Protein