Increased serum caspase-1 in adult-onset Still’s disease

doi:10.21203/rs.3.rs-3757786/v1

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Increased serum caspase-1 in adult-onset Still’s disease

https://doi.org/10.21203/rs.3.rs-3757786/v1

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published 28 Jul, 2024

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Background

Caspase-1 is an essential component in the inflammasome activation cascade. This study assessed the potential of serum caspase-1 level as an inflammatory biomarker in patients with adult-onset Still’s disease (AOSD).

Methods

The study included 51 consecutive patients diagnosed with AOSD based on the Yamaguchi criteria, 66 patients with rheumatoid arthritis (RA) as a disease control, and 36 healthy subjects. Serum concentrations of caspase-1 were measured using enzyme linked immunosorbent assay (ELISA). In AOSD patients, the serum levels of 69 cytokines were analyzed using a multi-suspension cytokine array, and a cluster analysis of each cytokine was performed to identify specific molecular networks.

Results

AOSD patients had significantly increased serum caspase-1 levels versus RA patients (p < 0.001) and healthy subjects (p < 0.001). Serum caspase-1 also had significant positive correlations with AOSD disease activity score (Pouchot score r = 0.59, p < 0.001) and serum ferritin (r = 0.54, p < 0.001). Furthermore, among AOSD patients, significant correlations existed between serum caspase-1 and inflammatory cytokines, including IL-18. On immunoblot analysis, the cleaved form of caspase-1 (p20) was detected in the serum of untreated AOSD patients not in those from inactive AOSD patients receiving immunosuppressive treatments.

Conclusions

Caspase-1 can be a useful biomarker for the diagnosis and monitoring of AOSD. Activation of caspase-1 could be correlated with the inflammatory component of AOSD, specifically through the induction of proinflammatory cytokines via inflammasome activation cascades.

Adult-onset Still`s disease

Caspase-1

Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory disease accompanied by a broad spectrum of clinical manifestations [1]. Although its pathogenesis is not fully understood, inflammasome activation is thought to be involved [2]. Activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain 3 (NLRP3) inflammasomes trigger capase-1 activation, which converts pro-IL-1β and pro-IL-18 into their mature forms [3]. Excessive inflammasome activation results in the overproduction of IL-1β and IL-18 in autoinflammatory disorders [4]. Because of this, IL-1β and IL-18 produced by innate immune cells through inflammasome activation are implicated in the autoinflammatory processes in AOSD [5].

Caspase-1 is the prime member of the inflammatory caspases; it activates pro-IL-1β or pro-IL-18 [6]. During the inflammasome activation processes, activated caspase-1 may lead to the processing of IL-18 and IL-1β into mature forms, which play an important role in cytokine cascades in AOSD [7]. Previous studies demonstrated that serum caspase-1 was elevated in patients with inflammatory disorders, including neurological or hepatic diseases [8, 9]. However, whether caspase-1 can be used as a serum biomarker for autoinflammatory disorders is unknown, and the role of caspase-1 in rheumatic diseases has not been clearly defined. In this study, we investigated the clinical relevance of caspase-1 as an autoinflammatory biomarker in AOSD, given the importance of inflammasomes in its pathogenesis. We analyzed the serum levels of casapase-1 in patients with AOSD versus patients with rheumatic arthritis (RA) and healthy controls (HCs). We also investigated the clinical correlations of caspase-1 with inflammatory cytokines and disease parameters in patients with AOSD. Our findings revealed that serum caspase-1 was elevated in AOSD patients and that elevated caspase-1 was correlated with systemic scores and inflammatory cytokines including IL-18 in AOSD patients.

A total of 51 untreated patients with AOSD who were treated ar Fukushima Medical University Hospital Department of Rheumatology between January 1995 and April 2020 were enrolled in this study. All patients included had to be 17 years or older to be diagnosed with AOSD according to Yamaguchi’s diagnostic criteria [10] after excluding those with infectious, neoplastic, and autoimmune disorders.

We additionally collected serum samples from 18 treated AOSD patients at the time of remission in order to explore the longitudinal changes. As controls, 36 HCs (12 males, 24 females, median age 39 years, interquartile range [IQR]; 32–45 years) were included. HCs lacked chronic medical diseases or conditions and did not take prescription medications or over-the-counter medications within seven days. Additional independent sets consisting of 66 patients with rheumatoid arthritis (RA) were used to determine the specificity of the values of caspase-1 in AOSD patients. Patients diagnosed with RA in Fukushima Medical University Hospital were randomly selected. The study was approved by the institutional review boards of Fukushima Medical University (No. 2021 − 290), and the National Center for Global Health and Medicine (NCGM-G-003472). An opt-out strategy was chosen for the participants, and those who declined to provide informed consent were excluded.

ELISA methods

Serum concentrations of caspase-1 were measured using enzyme–linked immnunosorbent assay kit (R&D Systems, Minneapolis, MN, USA) according to the manufacturer’s instructions. The mean of minimum detectable dose (MDD) in this study was < 0.20 pg/m.

Chemokine and cytokine measurements

The multiplex assay of humoral factors was determined by Bio-Plex 3D system (Bio-Rad, Hercules, CA) according to the manufacturers’ instructions. Briefly, serum samples were assayed using a Bio-Rad 3D and Bio-Plex Pro Wash Station equipped with a magnetic manifold. Cytokine levels in assayed samples were derived from the standards run for each assay plate and reported as serum cytokines/chemokines in pg/mL A total of 67 humoral factors were quantified by the Bio-Plex 3D system (Bio-Rad, Hercules, CA) and the HISCL-5000 (Sysmex Corp., Kobe, Japan) according to the manufacturers’ instructions.

Immunoblot analysis

Human serum samples were diluted 10-fold with PBS. We separated this diluted human serum sample (total serum amounts: 2µl) plus 5 µl of protein loading buffer by NuPAGE 3–8% Tris-acetate gel electrophoresis (Invitrogen, Carlsbad, CA, USA). Proteins were electrophoretically transferred onto an Invitrogen polyvinylidene fluoride membrane and incubated overnight at 4°C with blocking solution [5% non-fat milk in Tris-buffered saline with 0.05% Tween 20 (TTBS)]. The blocked membrane was incubated with rabbit anti-human capase-1 (full length p48, D7F10, Cell Signaling Technology, Boston, MA, USA) antibody or cleaved caspase-1 antibody (p20 D57A2, Cell Signaling) at 1:1000 dilution with 1% non-fat milk in TTBS for 1 h at room temperature and then washed five times with TTBS buffer for 10 min each time at room temperature with constant shaking. Then the membrane was incubated with horseradish peroxidase-conjugated second antibody (1:3000 dilution; Santa Cruz Biotechnology, Dallas, TX, USA) for 1 h at room temperature and washed five times with TTBS buffer for 10 min each time at room temperature with constant shaking. Immunodetection analysis was performed using an electrochemiluminescence western blotting kit (Amersham, Little Chalfont, UK). Images of the developed film were scanned using an LAS-3000 image analyzer (Fujifilm, Tokyo, Japan).

Statistical analysis

Data are presented as medians and interquartile ranges for continuous variables and as frequencies and percentages for qualitative variables. Correlations between pairs of serum markers were calculated using Spearman’s rank correlation test. To rank the cytokine levels, we per- formed the multivariate classification algorithm of random forest analysis (RFA) using the R package RandomForest (http://cran.r-project.org/web/packages/randomForest/) version 4.6.12 software, as previously described [11]. Mann-Whitney's U test were used to compare group differences. Wilcoxon signed-rank tests were used to evaluate changes pre- and post-treatment. Statistical analyses were performed using R software (version 4.3.1) and SPSS Statistics software (version 29.0; IBM Corp., Armonk, NY, USA). All reported p-values were two-sided, and P < 0.05 was considered statistically significant. Bonferroni's correction was applied to the multiplex analysis.

Demographic data of patients with AOSD

This study included 51 patients with AOSD (88.2% female; median age: 40 years, IQR [28–56]), whose serum samples were collected in the active state. The laboratory parameters include a complete blood count, liver function tests, C-reactive protein (CRP), and ferritin. The baseline characteristics and laboratory data are summarized in Table 1. The principal clinical symptoms included a high spiking fever 68.9%), skin rash (57.8%), arthralgia (57.8%), sore throat (38.9%), and splenomegaly (37.8%). Patients with AOSD had elevated median levels of biological markers that were representative of disease activity, such as CRP (median: 6.8 mg/dl, IQR [2.9–10.9]) and ferritin (median: 1,159 pg/ml, IQR [310–3,887]).

Table 1
Demographic and clinical characteristics of patients with AOSD
Variables	n = 51
Female, n (%)		36 (70.6)
Age at AOSD diagnosis (years), median (IQR)		46 (30–62)
Ferritin at diagnosis (ng/mL), median (IQR)		2,764 (623-9,694)
CRP at diagnosis (mg/dL), median (IQR)		7.13 (2.95–11.2)
WBC at diagnosis (/µL), median (IQR)		9,900 (7,300 − 13,800)
AST at diagnosis (U/L), median (IQR)		87 (54–187)
ALT at diagnosis (U/L), median (IQR)		35 (27–94)
Pouchot`s score		3 (2–5)
Monocyclic type, n (%)		18 (35.3)
Polycyclic systemic type, n (%)		30 (58.8)
Chronic articular type, n (%)		1 (1.9)
MAS, n (%)		8 (15.7)
All data are expressed as median (IQR), or numbers (percentages).
IQR: interquartile range, AOSD: adult onset Still's disease, CRP: C-reactive protein, WBC: white blood cell, AST: aspartate aminotransferase, ALT: alanine aminotransferase, MAS: macrophage activation syndrome.

Demographic data of patients with RA

The study included 66 patients with RA. 39 patients (78.0%) were female, and their median age was 67 years [IQR]; 62–74 years. 8 patients (16%) of RA were untreated. Most of the RA patients were taking disease-modifying anti-rheumatic drugs (DMARDs), mostly methotrexate (26/50, 52%), and biologics (17/50, 34%). The median DAS28-CRP was 2.74 (IQR; 2.19–3.62), and the median DAS28-ESR was 3.43 (IQR; 2.96–4.03).

Serum levels of caspase-1 in patients with AOSD

Serum levels of caspase-1 were determined using ELISA in patients with AOSD, patients with RA, and HCs. Patients with AOSD had significantly higher caspase-1 (median: 419.33 ng/ml, IQR [79.19-555.84]) compared to patients with RA (6.98 ng/ml, p < 0.001) and HCs (5.85 ng/ml, p < 0.001) (Fig. 1).

We also evaluated the correlations of serum caspase-1 with various clinical parameters in patients with AOSD. Although serum caspase-1 did not correlate with leucocyte counts or transaminases, it was significantly correlated with serum ferritin and the Pouchet score (Fig. 2), which correspond to the disease activity of AOSD [12].

To explore the longitudinal changes in caspase-1, we included 18 patients with 2 longitudinal samples (at least 1 month apart). In the longitudinal study, 8 patients with active AOSD were followed until they became inactive, then they were resampled. Serum caspase-1 levels significantly decreased (Fig. 3) alongside ferritin and Pouchot’s score after immunosuppressive treatments.

Correlation between serum caspase-1 and inflammatory cytokines and chemokines in AOSD

A total of 71 cytokines (6Ckine/CCL21, BCA-1/CXCL13, CTACK/CCL27, ENA-78/CXCL5, eotaxin-2/CCL24, eotaxin-3/CCL26, eotaxin/CCL11, fractalkine/CX3CL1, GCP-2/CXCL6, GM-CSF, Gro-α/CXCL1, Gro-β/CXCL2, IFN-γ, I-309/CCL1, I-TAC/CXCL11, IL-10, IL-12/IL-23 p40, IL-16, IL-1β, IL-2, IL-4, IL-6, IL-8/CXCL8, IP-10/CXCL10, MCP-1/CCL2, MCP-2/CCL8, MCP-3/CCL7, MCP-4/CCL13, MDC/CCL22, MIF, MIG/CXCL9, MIP-1α/CCL3, MIP-1δ/CCL15, MIP-3α/CCL20, MIP-3β/CCL19, MPIF-1/CCL23, SCYB16/CXCL16, SDF-1α + β/CXCL12, TARC/CCL17, TECK/CCL25, TNF-α, basic FGF, G-CSF, HGF, IFN-α2, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17, IL-18, IL-1α, IL-1Ra, IL-2Ra, IL-3, IL-5, IL-7, IL-9, LIF, M-CSF, MIP-1β, PDGF-BB, RANTES, SCF, SCGF-β, TNF-β, TRAIL, VEGF, β-NGF, IFN-λ3, and TARC) were measured in patients with AOSD and analyzed for their correlations with caspase-1. Cytokine expression profiles were analyzed by heat map (Fig. 4); those clustered in group 1 have positive correlations with caspase-1: Eotaxin, HGF, IFN-α2, IFN-g, IL-12p40, IL-13, IL-15, IL-18, IL-2, IL-2Ra, IL-3, IL-5, IL-6, and IP-10. Among these cytokines, 17 cytokines (MIP-3α/CCL20, IL-3, MIP-3β/CCl19, LIF, IL-2Ra, I-TAC/CXCL11, Basic FGF, 6Ckine/CCL21, MIF, IL-2, IL-1Ra, TECK/CCL25, CCL1, M-CSF, TNF-α, G-CSF, IL-18) were positively correlated with caspase-1 after Bonferroni`s correction (Table 2).

Table 2
The correlations between serum cytokines and caspase-1 in AOSD patients (after Bonferroni`s correction).
	correlation coefficient	P value
MIP-3a/CCL20	0.7849	< 0.001
IL-3	0.7169	< 0.001
MIP-3β/CCL19	0.7029	< 0.001
LIF	0.6683	< 0.001
IL-2Ra	0.6441	< 0.001
I-TAC/CXCL11	0.6385	< 0.001
BasicFGF	0.6251	< 0.001
6Ckine/CCL21	0.6174	< 0.001
MIF	0.6125	< 0.001
IL-2	0.5865	< 0.001
IL-1Ra	0.5862	< 0.001
TECK/CCL25	0.5852	< 0.001
CCL1	0.5719	< 0.001
M-CSF	0.5642	< 0.001
TNF-α	0.5542	< 0.001
GM-CSF	0.5419	< 0.006
IL-18	0.5361	< 0.012
AOSD: adult onset Still's disease, MIP: macrophage inflammatory protein, CCL: chemokine (C-C motif) ligand, IL: interleukin, LIF: leukemia inhibitory factor, I-TAC: interferon-inducible T cell alpha chemoattractant, CXCL: chemokine (C-X-C motif) ligand, FGF: fibroblast growth factor, MIF: macrophage migration inhibitory factor, TECK: thymus expressed chemokine, M-CSF: macrophage colony-stimulating factor, TNF: tumor necrosis factor.

Detection of circulating cleaved caspase-1 in untreated AOSD patients

To detect the circulating caspas-1, serum samples from AOSD patients were subject to immunoblot analysis using anti-full-length caspase-1 antibody. Single band with the molecular weights (45kDa) were detected in the sera from AOSD patients as well as in those from healthy subjects suggesting that they originated from the heavy chain of serum-containing IgG. However, full-length caspase-1 band (p48) was not detected in serum from AOSD patients (Fig. 5A). Caspase-1 activation occurs during its release; it is not an intracellular event in response to exogenous inflammasome activation [13]. Extracellular caspase-1 is induced during its cleavage step in pro-IL-1β processing [14]. Therefore, immunoblot analysis using anti-cleaved IL-1β antibody (p20) were performed. Cleaved casapae-1 bands with a MW of 20 kDa just below the light chain (p25) of serum-containing IgG was detected on the sera of untreated AOSD patients not in healthy subjects on immunoblot analysis. However, cleaved caspase-1 was not detected in the sera of untreated AOSD patients, which was diminished in the paired sera after treatment (Fig. 5B).

Inflammasomes are multiprotein complexes which serve as pattern recognition receptors in the immune system [15]. Upon the sensing pathogen-associated molecular patterns, inflammasomes can be activated by recruiting and activating caspase-1 [16]. Activated caspase-1 converts precursors of IL-1β and IL-18 into their mature forms [3], thus playing an important role in the pathogenesis of autoinflammatory diseases [17]. In this study, ELISA analysis demonstrated that significantly higher levels of caspase-1 were found in active AOSD patients, and the elevated caspase-1 levels were correlated with serum ferritin and the Pouchet score, which are the systemic activation markers for AOSD. Furthermore, serum caspase-1 was also correlated with serum IL-18, which is a crucial mediator maturated by inflammasomes and is presumed to be an AOSD-specific biomarker. The correlation of caspase-1 with the disease activity scores for AOSD suggests that the elevated levels of caspase-1 may reflect the inflammasome activation status, which is implicated in the pathogenesis of AOSD. Taken together, caspase-1 can serve as a novel biomarker for evaluating and monitoring AOSD disease activity.

Inflammasomes are composed of three main components: NLRP3, ASC (an adaptor protein termed as apoptosis-associated speck-like protein containing a caspase recruitment domain), and pro-caspase-1, which mounts an inflammatory response against cellular damage [18]. Activation of the inflammasomes, in turn, promotes the activation of caspase-1 [19]. Activated caspase-1 cannot be detected endogenously in the cytosol of innate immune cells upon the activation of inflammasomes [20]. However, the cleaved caspase-1 subunit can be detected, indicating that mature caspase-1 is released along with processed IL-1β and IL-18 during the inflammasome activation cascade and serves as a marker for inflammasome activation [21]. Activated caspase-1 triggers the cleavage of Gasdermin D (GSDMD) and pro-IL − 1β or pro-IL-18 [22]. The cleaved GSDMD promotes pore formation in the plasma membrane and further facilitates the release of these inflammatory mediators [23]. In line with this, we also examined the sera of AOSD patients for cleaved caspase-1 using immunoblot analysis. Indeed, we demonstrated that the cleaved form of caspase-1, p20, was detectable in the serum of AOSD patients. Active AOSD patients had markedly increased expression of caspase-1 with its cleaved form. However, the cleaved form of caspase-1 was exclusively found in untreated AOSD patients, and it was undetectable among AOSD patients in the remission state receiving immunosuppressive therapy. Pyroptosis, a caspase-1-dependent type of programmed cell death, was recently found to promote the secretion of IL-1b and IL-18 during the inflammatory response [24]. Caspase-1 has also been reported to activate the transcription factor NF-kB independent of its enzymatic activity, which may result in inflammation in vivo [25]. This suggests the presence of cross-talk between blood caspase-1 and the inflammatory mediators in the inflammatory disorder. Taken together, it is possible that caspase-1 has a potential role in inflammatory cascades by enhancing inflammatory cytokine production.

Recent studies have confirmed that IL-1b or IL-18 activation by caspase-1 is directly associated with inflammatory environments [26]. Overexpressed caspase-1 has been demonstrated in aortas of patients with coronary atherosclerosis [27]. In autoinflammation, caspase-1 can be widely activated in endothelial cells and circulating innate immune cells [28]. However, the role of caspase-1 in AOSD has not been clarified. In our study, upregulated circulating caspase-1 was linked with inflammasome activation in AOSD. These findings suggest that, in AOSD, serum caspase-1 can reflect the activation status of circulating innate immune cells. Caspase-1-dependant inflammasome activation contributes to the autoinflammatory process in AOSD, which aggravates the maturation and release of proinflammatory cytokines, IL-1β and IL-18.

Our study has several limitations. First, multivariate analysis could not be performed due to the small sample size. The number of AOSD patients for analysis was small as well. Second, multiple serum cytokines were measured in AOSD patients only, and not in control patients (RA) or healthy subjects. Third, the mechanism behind caspase-1 release was not completely elucidated. Further studies need a larger number of cases and innate immune cellular analysis, which can elucidate the mechanisms for the elevation of circulating caspase-1.

In conclusion, serum levels of caspase-1, a component of the inflammasome, was elevated in AOSD patients. Serum caspase-1 levels in AOSD patients significantly correlated with disease activity indices such as serum ferritin and Pouchet’s score, as well as with inflammatory cytokines, including IL-18. Thus, caspase-1 may be an effective biomarker for the diagnosis of AOSD and predicting disease activity. However, the early diagnosis and prognostic value of caspase-1 in AOSD patients requires further validation with large-sample studies.

AOSD

Adult-onset Still’s disease

CCL

Chemokine (C-C motif) ligand

CRP

C-reactive protein

CTACK

Cutaneous T-cell attracting chemokine

CXCL

Chemokine (C-X-C motif) ligand

CX3CL1

CX3CR1-ligand

ESR

erythrocyte sedimentation rate

DMARDs

Disease-modifying anti-rheumatic drugs

FGF

Fibroblast growth factor

GCP

Granulocyte chemotactic protein

G-CSF

Granulocyte colony-stimulating factor

GM-CSF

Granulocyte macrophage colony-stimulating factor

Gro

Growth-regulated protein

GSDMD

Gasdermin D

HGF

Hepatocyte growth factor

Interleukin

IFN

Interferon

Interferon γ-induced protein

IQR

Interquartile range

I-TAC

Interferon-inducible T cell alpha chemoattractant

LIF

Leukemia inhibitory factor

MAS

Macrophage activation syndrome

M-CSF

Macrophage colony-stimulating factor

MCP

Monocyte chemotactic protein

MDC

Macrophage-derived chemokine

MIF

Macrophage migration inhibitory factor

MIG

Monokine induced by interferon-γ

MIP

Macrophage inflammatory protein

MPIF

Myeloid progenitor inhibitor factor

NGF

Nerve growth factor

PDGF

Platelet derived growth factor

Rheumatoid arthritis

RANTES

Regulated on activation, normal T cell expressed and secreted

RFA

Random forest analysis

ROC

Receiver operator characteristic

SCYB16

Small-inducible cytokine B16

SCF

Stem cell factor

SCGF

Stem cell growth factor

SDF

Stromal derived factor

TARC

Thymus and activation-regulated chemokine

TECK

Thymus-expressed chemokine

T helper type

TNF

Tumor necrosis factor

TRAIL

TNF-related apoptosis-inducing ligand

VEGF

Vascular endothelial growth factor

Ethical Approval and Consent to participate

Ethical approval for this study was provided by the Ethics Committee of Fukushima Medical University (No.2021-290) and the National Center for Global Hearth and Medicine (No. NCGM-187)

Consent for publication

An opt-out strategy was selected for the participants, and those who declined to provide informed consent were excluded.

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

KM has received research grants from Chugai, Pfizer, and AbbVie. Rest of the authors declares that they have no competing interests.

Funding

The study was supported by the Japan Grant-in-Aid for Scientific Research (20K08777).

Authors' contributions

HM, SY, NM, YF, YS, KS, SS, and TA were involved in acquiring clinical data. HM, SY, and KM drafted the manuscript and conducted molecular biochemical studies. MM, MS, and KM participated in the sequence alignment and drafted the manuscript. HM, SY, MM, MS, and KM participated in the study design. HM, SY, MM, MS, and KM performed the statistical analysis and interpretation of data. All authors read and approved the final manuscript.

Acknowledgments

We are grateful to Ms. Kanno Sachiyo for her technical assistance in this study.

Authors’ information

¹Department of Rheumatology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima 960–1295, Japan

²Department of Immunology and Rheumatology, Division of Advanced Preventive Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan

³Genome Medical Sciences Project, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan

⁴ Department of Viral Pathogenesis and Controls, National Center for Global Health and Medicine, 1-7-1 Kohnodai, Ichikawa, Chiba 272-8516, Japan

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No competing interests reported.

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Increased serum caspase-1 in adult-onset Still’s disease

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Abstract

Background

Methods

Results

Conclusions

Figures

Introduction

Patients

ELISA methods

Chemokine and cytokine measurements

Immunoblot analysis

Statistical analysis

Results

Demographic data of patients with AOSD

Demographic data of patients with RA

Serum levels of caspase-1 in patients with AOSD

Correlation between serum caspase-1 and inflammatory cytokines and chemokines in AOSD

Detection of circulating cleaved caspase-1 in untreated AOSD patients

Discussion

Abbreviations

Declarations

References

Additional Declarations

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