Neutrophil extracellular traps formation and citrullinated histones 3 level in patients with Kawasaki disease

doi:10.21203/rs.3.rs-2303527/v1

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Neutrophil extracellular traps formation and citrullinated histones 3 level in patients with Kawasaki disease

https://doi.org/10.21203/rs.3.rs-2303527/v1

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Background: Kawasaki disease (KD) is a vasculitis associated with vascular injury and autoimmune response. Vascular endothelial injury plays a key role in the occurrence and development of vasculitis in Kawasaki disease. In this study, we sought to determine the change of neutrophil extracellular traps (NETs) and Citrullinated histone 3(H3Cit )in KD.

Methods: The children with KD in our hospital were recruited,2ml of peripheral venous blood was taken before accept treatment, and sent for examination of NETs by flow cytometry. The level of H3Cit was measured by enzyme-linked immunosorbent assay.

Results: Compared to the healthy control group, the count of NETs in acute KD group were significantly increased (P<0.01). The level of H3Cit was significantly higher in acute KD group than that in healthy control subjects. Of note, in comparation with acute KD group, the counts of NETs and the level of H3Cit were both decreased in KD patients treated with IVIG (P<0.01).

Conclusions: Acute KD is characterized by increased formation of NETs and high level of H3Cit. Intravenous immunoglobulin (IVIG )significantly inhibited NETs formation and also reduce the level of plasma H3Cit in children with KD

Kawsaki disease

neutrophil extracellular traps

Citrullinated histone 3

IVIG

KD is a kind of systemic self-limited vasculitis, is associated with vascular injury and autoimmune response[1].It has become the leading cause of acquired heart disease in children[2].In 2020, The number of children with KD and Kawasaki like disease after COVID-19 infection increased significantly in some[3, 4]. The efficacy of IVIG administered in the acute phase of KD is well-established, But,the immune mechanism of IVIG has not been fully revealed. However, the etiology and the true worldwide incidence, morbidity, and mortality will remain unknown until a diagnostic test is developed[5, 6].In 2004, the American Heart Association proposed that KD is a risk factor for coronary heart disease in adulthood[7].Therefore, the persistent vascular endothelial injury and dysfunction of KD are closely related to the long-term clinical outcome[8].Neutrophils present in vascular endothelial cells and participates in inflammatory reactions[9, 10].Our previous experiments demonstrated that the activation of neutrophil may play a significant role in the pathogenesis of coronary arterial lesion (CAL) in KD[11].

Neutrophils produce web-like structures composed of decondensed chromatin and antimicrobial proteins called neutrophil extracellular traps (NETs), which can neutralize and eliminate pathogens to prevent them from spreading[12].More and more evidence shows that NETs serving as effective antimicrobial defenses, but also as putative sources of molecules with immune effector and proinflammatory roles. In susceptible individuals, NETs may be the autoantigen of various autoimmune diseases may promote tissue damage and autoimmunity[13].In various lung diseases, cancer and cardiovascular diseases, the excessive production and/or reduction of degradation of NETs play a key role in the initiation and persistence of autoimmune response and organ damage[14–16].Since KD is related to vascular injury and autoimmune response, NETs may be involved in the pathophysiology of KD. Citrullinated histone 3 (H3Cit) is one of the main protein components of neutrophil extracellular traps and has been shown to be highly involved in the process of NETs[17]. H3Cit has been considered to be a good biomarker of NETs. H3Cit can be used as a therapeutic target in septic mice and can reduce the inflammatory response of sepsis[18].H3Cit is secreted in the form of micro vesicles and affects the circulatory system by binding with platelets[19].It plays a certain role in thrombotic diseases and microcirculatory disorders[20]. Nevertheless, the role of H3Cit in the pathogenesis of KD has not been clarified.

The primary objective of this study was to investigate (1) the changes of NETs formation and H3Cit level in KD patients with or without IVIG treatment, (2) the relationship between NETs and H3Cit.

Patients and sample collection

The children with KD were recruited from January 2020 to December 2020. The diagnostic basis was based on the standards revised by the fifth KD Committee of Japan. Children with a disease course of more than 10 days or who have been treated with human immunoglobulin are not included. All the patients have excreted infection with COVID-19. Once patients met the diagnostic criteria of KD, all of them were treated with oral aspirin (30-50mg/kg per day), IVIG (2 g/kg per day) immediately.Patients who had resolution of fever (< 37.5°C) for 48h after finishing the initial IVIG treatment, C-reactive protein < 20mg/L were considered to be sub-acute KD, Patients who have a course of disease more than 10 days or have been treated with IVIG were not included. For the healthy control group, patients with inguinal hernia and other selected surgery without any clinical symptoms and signs of inflammation or allergic purpura and other immune diseases were selected[21]. After admission, blood samples were taken from all acute and sub-acute KD patients and healthy control group subjects.

This study accord with the ethical standards formulated by the Committee in charge of human trials of Children’s Hospital of WUXI, was approved by the committee, and obtained the informed consent from the parents of all subjects.

Peripheral blood neutrophil extraction

2 ml of peripheral venous blood was taken from both acute and sub-acute KD subjects, and sent for examination of NETs within 2h using the flow cytometry. Neutrophil Extraction Kit included reagent A, reagent C, cell washing solution、erythrocyte lysis buffer was used for peripheral blood poly- morphonuclear neutrophil (PMNs) isolation. First add 4ml of reagent A into the centrifuge tube, take 2ml of fresh anticoagulant whole blood, and then carefully overlay 2ml of reagent C on reagent A to form a gradient interface. Lay the blood above the liquid level of the separation solution, and pay attention to keep the interface between the two liquid levels clear; Room temperature, 500 ~ 1000g, centrifugation for 20 ~ 30min;After centrifugation, there will be two layers of annular milky white cells in the centrifuge tube, the upper cells are mononuclear cells and the lower cells are neutrophils; Carefully suck the neutrophils between reagent C and reagent A and in reagent A into a 15ml clean centrifuge tube with a pipette, and wash with 10ml PBS or cell washing solution; Discard the supernatant, resuspend the cells with 5ml PBS or cell cleaning solution, 2500g, and centrifuge for 10min for twice; Suspend and discard cells.

Flow Cytometry Measured NETs Production

The flow cytometry protocol was adapted from the protocol published by Gavillet M. et al[22].PMN, were seeded at a density of 1 × 105/100 µl in 24 hole plate ,take out the 24 well plate, directly add 1ml of 4% paraformaldehyde and fix it for 20min (BALF can start directly from this step)one 12000g, centrifugation for 20min, and discard the supernatant; Wash PBS with 1ml, centrifuge for 20min, and discard the supernatant; Resuspend to 100ul;Add anti-Histone 3 pS28-APC(130-105-701, h&m,30 tests) at 1:300 dilution, and FITC-conjugated anti-myeloperoxidase(MPO) antibody (ab90812-50ug [2D4] ) analyzed by flow cytometry; Keep away from light and room temperature for 30min;Add 1ml PBS for cleaning, centrifuge for 20min, and discard the supernatant; incubated sequentially with the resuspended in 2% BSA and analyzed by flow-cytometry according to the gating strategy detailed by Gavillet M. MPO- and anti-H3-Histone-antibody-positive cells were defined as surrogates for NETs.

H3Cit ELISA

2 ml of peripheral blood was anticoagulated with EDTA,centrifuged at 4 ℃ × 3000 g for 20 minutes, taken the supernatant and frozen at -80℃ for the measurement of H3Cit using enzyme-linked immunosorbent assay. Citrullinated histone 3 (H3Cit) was analysed by a commercial sandwich ELISA kit (Cayman Chemical, Ann Arbor, Michigan, USA 501620-96wells) and performed according to the manufacturer. This H3Cit assay employed a monoclonal antibody specific for histone H3 citrullinated at R2, R8, and R17 (clone 11D3) .

Statistics Analysis

BD facsdiva version 6.1.3 (BD Biosciences, NJ, US) software was used on BD facscanto II (BD Biosciences, NJ, US), and flowj (BD, US) was used to analyze the flow-cytometry data. Analyses were carried out using Statistical software pack- age version 12.5 (TIBCO Inc). Data of NETs are presented as means ± SEM, Date of H3Cit were reported as median and inter- quartile range. For statistical analysis of differences between the study groups, the Kruskal–Wallis test was performed followed by the Mann Whitney test for analysis of intergroup differences. Results were considered significant at P (*p ≤ 0.05, **p ≤ 0.01)

IVIG inhibited NETs formation in KD group

All blood samples of 7 KD patients (3 male/4 female) and 7 healthy control subjects were collected both before and after IVIG injection. There are no significant differences in gender, age between these groups. The levels of White blood cell count /Neutrophils (%) and CRP in KD group was higher than that in healthy control (HC) group. The Platelet count of sub-acute KD was higher than that in acute KD and HC group, which was consistent with the characteristics of KD(Table 1).

Acute KD group (Fig. 1a) showed significantly higher NETs counts than sub-acute KD (Fig. 1b) (28.757 ± 6.336 vs 12.794 ± 2.804, P < 0.01) and HC groups (Fig. 1c) (12.794 ± 2.804 vs 10.973 ± 3.659, P < 0.01).After IVIG treatment, NETs counts were obviously decreased in KD patients. There is no significantly difference between sub-acute KD and HC group(Fig. 2).

IVIG down-regulated the level of H3Cit

The level of H3Cit in serum samples of 27 acute KD, 20 sub-acute KD patients and 20 healthy children were measured. Clinical and laboratory characteristics of subjects studied are given in Table 2. KD individuals were characterized by increased levels of CRP, White blood cell count and Platelet count.

The lever of H3Cit is significantly elevated in acute KD group in comparison to that in HC group (4.932(2.1,9.6) vs 1.320(1.1,3.0) ng/ml, p = 0.000). Besides, IVIG treatment significantly decreased the H3Cit level in KD patients (4.932(2.1,9.6) vs 1.556(1.3,2.5) ng/ml, P = 0.000). There was no significant difference between HC and sub-acute KD group (1.556(1.3,2.5) vs 1.320(1.1,3.0)ng/ml, P = 0.534).(Fig. 3)

KD is associated with innate immune disorders. The levels of a variety of cytokines are elevated in KD patients[2]. NETs take the central stage in driving autoimmune. It increases TNF-α, interleukin-1β, and hypoxia-inducible factor- 1α mRNA expression in humans[24].NETs can also activate other immune cells, such as T cells, B cells, antigen-presenting cells. KD is also a thrombotic disease. Coronary artery aneurysm with thrombosis is the most dangerous among various complications of KD in sub-acute and convalescent.Studies have shown that the levels of DNA histone complex and free DNA (cf-DNA), the key components of NETs, are increased in a variety of thrombotic cardiovascular diseases, and as a sensitive biomarker, they are positively correlated with the severity of the disease[25, 26]. More and more studies have shown that NETs can promote coagulation. NETs has established a close relationship between inflammation and thrombosis. NETs can over-activate coagulation and lead to disseminated intravascular coagulation[27–29].While the external pathway is stimulated by NETs presented by tissue factors, and platelets are strongly activated by DNA / histone complexes[30].The main interactions between platelets, coagulation system components and NETs have been gradually clarified, forming a new concept called immunothrombosis. Therefore, we consider that the immune response of KD may have a common immune mechanism with the production of NETs.

In this study, we quantified NETs generation in patients with KD by flow cytometry-based approach. Results showed that NETs counts in acute KD group was significant higher than that in HC group, indicating that NETs formation may be involved in the pathogenesis of KD. Yoshida et al found that the serum levels of cfDNA measured by a cell death detection elisa were significantly higher in the acute phase of KD than in the convalescent phase or HC [31]. However, Jing et al suggested that the formation of NETs may alter the biologic responses of PBMC and affect the vascular injury in KD [32]. These findings were in consisitent with our results.

The efficacy of IVIG therapy on patients with KD has been established. But the mechanism by which high-dose immunoglobulin ameliorates the vasculitis of KD remains obscure. It includes Fc-mediated inactivation of macrophages, consumption of activated complement proteins, neutralization of pathogenic autoantibodies by idiotype antibodies, and correction of cytokine imbalance et al[33]. In this study, we found that after IVIG treatment, the level of NETs was significantly decreased in KD patients, indicating that IVIG may reduce the immune response of KD by inhibiting the NETs formation. However, the precise mechanism by which IVIG suppresses NETs formation remains unknown. Okubo et al. recently demonstrated that IVIG-induced lactoferrin secretion, at least in part, can be involved in the IVIG-mediated inhibition of NETs formation[34–36].Further prospective clinical studies are needed to demonstrate the inhibitory effect of IVIG on NETs.

Our findings demonstrate that the level of H3Cit is significantly elevated in acute KD. Jamie E et al. found that H3Cit can directly contribute to inflammatory injury by disrupting the microvascular endothelial barrier [37]. H3Cit peptide has been proved to increase the permeability of HUVEC in vitro. It is also reported that histones may directly lead to inflammatory injury through host tissue injury [38, 39]. Increased levels of citrullinated histone H3 in patients with juvenile idiopathic arthritis (JIA) was reported by Parackva could contribute to ongoing inflammation associated with an autoimmunity, which can be ameliorated by regulating inflammation using immune therapy [40]. Therefore, we have a hypothesis that H3Cit may participate in vascular endothelial cells damage, which increases the vascular permeability, and leads to further damage of small and medium-sized blood vessels in KD. Certainly, this hypothesis needs to be verified by further biological and clinical experiments.Arginine deaminase type 4 (PAD4) is transferred to the nucleus after activation to induce citrullination of histone, leading to chromatin depolymerization, thus further increasing the production of NETs. Therefore, NETs and H3Cit have positive feedback interaction[41].In our study, we found that the the level change of NETs and H3Cit were consistent.

Our study has limitations. Firstly, sample size is relatively small. Particularly, because of the high requirements for specimen preparation, the sample size of NETs is relatively small. Secondly, the data of recovery period of KD are not included, and statistical associations might not necessarily indicate cause-effect relationships. Finally, a clinical relevance of increased serum H3Cit in relation to KD course, or vascular outcomes remains to be established.

In conclusion, acute KD is characterized by increased formation of NETs and high level of H3Cit. IVIG may reduced the level of H3Cit in KD patients by preventing NETs information so as to achieve therapeutic effect. These findings indicated that inhibiting H3Cit might be another potential therapeutic option for KD. Further studies on NETs and H3Cit will help improve our understanding of KD and accurate diagnosis, which remains challenging.

Author contributions

Jing Hu,Wei Qian, Jingjing Ling, and Shiying Zuo: conceptualization.Tao Xu and Liang Ju: formal analysis. Shiyinng Zuo and Jingjing Ling: funding acquisition. Wei Qian, Tao Xu, Liang Ju and Tianhe Wang: methodology. Jing Hu and Wei Qian: writing-original draft. Jing Hu, Jingjing Ling, and Shiying Zuo: writing-review and editing. All authors contributed to the article and approved the submitted version.

Fundings

This work was financially supported by the Scientific Research Project of Wuxi Health Commission (No.Q202010,MS201950);Wuxi Taihu Talent Plan Top Talents Project (No. BJ2020088) and Wuxi Taihu Senior Medical Team Project (GDTD202105).

Acknowledgements

We are very grateful to the families participating in this cohort study.

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Table.1.:Comparison of NETs detection data and clinical characteristics between three groups.

Table.2. Comparison H3cit detection data and clinical characteristics between three groups.

No competing interests reported.

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Neutrophil extracellular traps formation and citrullinated histones 3 level in patients with Kawasaki disease

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