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

Svanberg, Cecilia; Enocsson, Helena; Govender, Melissa; Martinsson, Κjell; Potempa, Lawrence A.; Rajab, Ibraheem M.; Fernández-Botrán, Rafael; Wetterö, Jonas; Larsson, Marie; Sjöwall, Christopher

doi:10.1016/j.jaut.2023.102998

Cited by 8 publications

(10 citation statements)

References 53 publications

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“…Thus, both cytokines, IL-17 and IL-6, which are critical than TNF-α in arthritis, are inhibited by CRP. The profiles of IL-1β, IL-2 and IL-10 reported here are also consistent with the previously published data ( 27 , 68 , 70 , 72 , 73 , 83 ) and CRP had no effect on these three cytokines.…”

Section: Discussionsupporting

confidence: 93%

“…That serum levels of IL-17 and TNF-a increase in CIA mice has also been reported previously (57,(70)(71)(72)(73)(74)(75)(76). CRP did not significantly affect TNF-a levels in the CIA mice reported here, but in vitro, CRP has been found to inhibit the production of TNF-a in IC-induced monocytes (68). mCRP, however, increases the production of TNF from monocytes cultured in vitro (77).…”

Section: B Asupporting

confidence: 88%

“…In the case of encephalomyelitis, it has been shown that CRP was protective by suppressing both Th1 response directly and Th17 response indirectly ( 60 ). CRP has also been shown to have immunosuppressive functions in IC-induced immune cells ( 68 ).…”

Section: Discussionmentioning

confidence: 99%

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C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice

Singh,

Prislovsky,

Ngwa

et al. 2024

Front. Immunol.

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The biosynthesis of C-reactive protein (CRP) in the liver is increased in inflammatory diseases including rheumatoid arthritis. Previously published data suggest a protective function of CRP in arthritis; however, the mechanism of action of CRP remains undefined. The aim of this study was to evaluate the effects of human CRP on the development of collagen-induced arthritis (CIA) in mice which is an animal model of autoimmune inflammatory arthritis. Two CRP species were employed: wild-type CRP which binds to aggregated IgG at acidic pH and a CRP mutant which binds to aggregated IgG at physiological pH. Ten CRP injections were given on alternate days during the development of CIA. Both wild-type and mutant CRP reduced the incidence of CIA, that is, reduced the number of mice developing CIA; however, CRP did not affect the severity of the disease in arthritic mice. The serum levels of IL-17, IL-6, TNF-α, IL-10, IL-2 and IL-1β were measured: both wild-type and mutant CRP decreased the level of IL-17 and IL-6 but not of TNF-α, IL-10, IL-2 and IL-1β. These data suggest that CRP recognizes and binds to immune complexes, although it was not clear whether CRP functioned in its native pentameric or in its structurally altered pentameric form in the CIA model. Consequently, ligand-complexed CRP, through an as-yet undefined mechanism, directly or indirectly, inhibits the production of IL-17 and eventually protects against the initiation of the development of arthritis. The data also suggest that IL-17, not TNF-α, is critical for the development of autoimmune inflammatory arthritis.

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Section: Discussionsupporting

confidence: 93%

Section: B Asupporting

confidence: 88%

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C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice

Singh,

Prislovsky,

Ngwa

et al. 2024

Front. Immunol.

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“…Our results showed that, in SLE and LN, serum CRP levels did not correlate with disease progression. The inability of CRP to reflect inflammatory activity in SLE could be explained by IFN1 gene overexpression or dysregulation, inhibitory effects of IFN1 IL-6/IL-1beta-induced CRP gene transcription, CRP’s proinflammatory/anti-inflammatory contradictory effects, the existence of several conformational isoforms, the presence of anti-CRP antibodies, polymorphisms (such as rs1205) in the CRP gene, multiple locations of protein synthesis (hepatocytes, kidney cells, neural cells, respiratory epithelial cells, adipocytes, leukocytes), and local conditions (acid microenvironment, NO release, IFN activation, proinflammatory cytokines, urea, heat, inflamed tissue, calcium, phospholipase A2, transcriptional activation of STAT3, C/EBP and NF-kB) [ 2 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. Many published reports investigating CRP as a biological response modifier in IFN-dependent conditions have shown that monomeric anti-CRP antibodies are associated with increased frequency and stimulation of IL-6 and TNF alpha production in LN [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

The Inflammatory Profile Orchestrated by Inducible Nitric Oxide Synthase in Systemic Lupus Erythematosus

Ene

Nicolae

2023

JPM

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(1) Background: The pathogenesis of systemic lupus erythematosus (SLE) involves complicated and multifactorial interactions. Inducible nitric oxide synthase overactivation (iNOS or NOS2) could be involved in SLE pathogenesis and progression. This study explored the relationship between NOS2-associated inflammation profiles and SLE phenotypes. (2) Methods: We developed a prospective, case control study that included a group of 86 SLE subjects, a group of 73 subjects with lupus nephritis, and a control group of 60 people. Laboratory determinations included serum C reactive protein (CRP–mg/L), enzymatic activity of NOS2 (U/L), serum levels of inducible factors of hypoxia 1 and 2 (HIF1a–ng/mL, HIF2a–ng/mL), vascular endothelial growth factor VEGF (pg/mL), matrix metalloproteinases 2 and 9 (MMP-2, MMP-9–ng/mL), thrombospondin 1 (TSP-1–ng/mL), and soluble receptor of VEGF (sVEGFR–ng/mL). (3) Results: CRP, NOS2, HIF-1a, HIF-2a, VEGF, MMP-2, and MMP-9 were significantly increased, while TSP-1 and sVEGFR were decreased in the SLE and lupus nephritis groups compared with the control group. The variations in these biomarkers were strongly associated with the decrease in eGFR and increase in albuminuria. (4) Conclusions: The inflammatory phenotype of SLE patients, with or without LN, is defined by NOS2 and hypoxia over-expression, angiogenesis stimulation, and inactivation of factors that induce resolution of inflammation in relation with eGFR decline.

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“…Recent advances emphasize that pCRP exhibits both proinflammatory and anti-inflammatory properties, whereas mCRP is exclusively proinflammatory ( 206 ). The interaction of pCRP with FcγRIIa demonstrates a protective effect against autoimmune diseases by reducing the type I interferon response triggered by immune complexes ( 207 ). Both pCRP and mCRP can induce thrombus formation, activate monocytes, platelets, and neutrophils, enhance the adhesion of neutrophils and monocytes to endothelial cells, and promote the formation of neutrophil-platelet and platelet-monocyte aggregates.…”

Section: Immunomodulation Of the Livermentioning

confidence: 99%

Interorgan communication with the liver: novel mechanisms and therapeutic targets

Zhao,

Zhang,

et al. 2023

Front. Immunol.

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The liver is a multifunctional organ that plays crucial roles in numerous physiological processes, such as production of bile and proteins for blood plasma, regulation of blood levels of amino acids, processing of hemoglobin, clearance of metabolic waste, maintenance of glucose, etc. Therefore, the liver is essential for the homeostasis of organisms. With the development of research on the liver, there is growing concern about its effect on immune cells of innate and adaptive immunity. For example, the liver regulates the proliferation, differentiation, and effector functions of immune cells through various secreted proteins (also known as “hepatokines”). As a result, the liver is identified as an important regulator of the immune system. Furthermore, many diseases resulting from immune disorders are thought to be related to the dysfunction of the liver, including systemic lupus erythematosus, multiple sclerosis, and heart failure. Thus, the liver plays a role in remote immune regulation and is intricately linked with systemic immunity. This review provides a comprehensive overview of the liver remote regulation of the body’s innate and adaptive immunity regarding to main areas: immune-related molecules secreted by the liver and the liver-resident cells. Additionally, we assessed the influence of the liver on various facets of systemic immune-related diseases, offering insights into the clinical application of target therapies for liver immune regulation, as well as future developmental trends.

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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

Cited by 8 publications

References 53 publications

C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice

C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice

The Inflammatory Profile Orchestrated by Inducible Nitric Oxide Synthase in Systemic Lupus Erythematosus

Interorgan communication with the liver: novel mechanisms and therapeutic targets

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