Proteomic and transcriptomic screening demonstrates increased mast cell–derived CCL23 in systemic mastocytosis

Söderlund, Stina; Bsc, Daryl Boey; Bsc, Wouter van Midden; Kjellander, Matilda; Sci, Kajsa Ax Biomed; Qian, Hong; Dahlin, Joakim S.; Ungerstedt, Johanna

doi:10.1016/j.jaci.2023.01.033

Cited by 6 publications

(6 citation statements)

References 34 publications

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“…[ 39 ] Additionally, positive correlation was found between plasma CCL23 levels and established indicators of the severity of systemic mastocytosis disease. [ 40 ] Reflexively, plasma Caspase 8, ADA and SIRT2 level negatively related to CP risk in our study. Caspase-8 is involved in the regulation of cell death mechanisms and immune responses in conditions like infection, autoimmunity, and T cell signal transduction.…”

Section: Discussionmentioning

confidence: 49%

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis

Yang,

Xu,

Liang

et al. 2024

Medicine

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It has been established that gut dysbiosis contributed to the pathogenesis of digestive disorders. We aimed to explore the causal relationships between intestinal microbiota, circulating inflammatory cytokines and chronic pancreatitis (CP). Summary statistics of genome-wide association studies (GWAS) of intestinal microbiome was retrieved from the MiBioGen study and the GWAS data of 91 circulating inflammatory cytokines and CP were obtained from the GWAS catalog. The 2-sample bidirectional Mendelian randomization (MR) analysis was performed between gut microbiota, circulating inflammatory cytokines and CP, in which the inverse variance weighted (IVW) method was regarded as the primary analysis approach. To prove the reliability of the causal estimations, multiple sensitivity analyses were utilized. IVW results revealed that genetically predicted 2 genera, including Sellimonas and Eubacteriumventriosumgroup, and plasm C-C motif chemokine 23 (CCL23) level were positively associated with CP risk, while genus Escherichia Shigella, Eubacteriumruminantiumgroup and Prevotella9, and plasma Caspase 8, Adenosine Deaminase (ADA), and SIR2-like protein 2 (SIRT2) level, demonstrated an ameliorative effect on CP. Leave-one-out analysis confirmed the robustness of the aforementioned causal effects and no significant horizontal pleiotropy or heterogeneity of the instrumental variables was detected. However, no association was found from the identified genera to the CP-related circulating inflammatory cytokines. Besides, the reverse MR analysis demonstrated no causal relationship from CP to the identified genera and circulating inflammatory cytokines. Taken together, our comprehensive analyses offer evidence in favor of the estimated causal connections from the 5 genus-level microbial taxa and 4 circulating inflammatory cytokines to CP risk, which may help to reveal the underlying pathogenesis of CP.

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Section: Discussionmentioning

confidence: 49%

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis

Yang,

Xu,

Liang

et al. 2024

Medicine

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“…In the current study, we found overall similar H3Cit-DNA levels in ISM compared to healthy, thus no signs of NET release as measured by H3Cit-DNA. This is perhaps not surprising as we 18 and others 25,26 have shown that most cytokine/chemokine levels are similar in ISM and healthy, which is also why it has been difficult to establish biomarkers for SM disease. 18 However, to our surprise, mean H3Cit-DNA levels in AdvSM, which are patients with an expected overall survival of 2-4 years 10,27 were also similar to healthy, although a great variation was seen.…”

Section: Discussionmentioning

confidence: 83%

“…This is perhaps not surprising as we 18 and others 25,26 have shown that most cytokine/chemokine levels are similar in ISM and healthy, which is also why it has been difficult to establish biomarkers for SM disease. 18 However, to our surprise, mean H3Cit-DNA levels in AdvSM, which are patients with an expected overall survival of 2-4 years 10,27 were also similar to healthy, although a great variation was seen. Recently, increased NET release has been demonstrated in patients with MPN 28,29 as well as when ex vivo stimulating chronic myeloid leukaemia patient cells with ionomycin or PMA, 30 and impaired NET release in peripheral blood of patients with MDS.…”

Section: Discussionmentioning

confidence: 83%

“…Single-cell transcriptomics data (gene expression counts) of low-density bone marrow cells as deposited on the Gene expression Omnibus database (GEO number GSE222830) was processed. 18 The batch-corrected data were re-clustered using the Leiden algorithm (resolution 0.2) to represent the cell types with finer resolution, and reannotated [19][20][21] in addition to previously annotated clusters.…”

Section: Methodsmentioning

confidence: 99%

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No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis

Rosell,

Karlström,

Dahlin

et al. 2023

Scand J Immunol

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In disease states with chronic inflammation, there is a crosstalk between mast cells and neutrophil granulocytes in the inflamed microenvironment, which may be potentiated by tryptase. In systemic mastocytosis (SM), mast cells are constitutively active and tryptase is elevated in blood. Mast cell activation in SM leads to symptoms from various organs depending on where the active mast cells reside, for example, palpitations, flush, allergic symptoms including anaphylactic reactions, and osteoporosis. Whether neutrophil function is altered in SM is not well understood. In the current study, we assessed nucleosomal citrullinated histone H3 (H3Cit‐DNA) as a proxy for neutrophil extracellular trap release in plasma from 55 patients with indolent and advanced SM. We observed a strong trend towards a correlation between leukocyte count, eosinophil count and neutrophil count and H3Cit‐DNA levels in patients with advanced SM but not in indolent SM; however, no differences in H3Cit‐DNA levels in SM patients compared with healthy controls. H3Cit‐DNA levels did not correlate with SM disease burden, tryptase levels, history of anaphylaxis or presence of cutaneous mastocytosis; thus, there is no evidence of a general neutrophil extracellular trap release in SM. Interestingly, H3Cit‐DNA levels and leukocyte counts were elevated in a subgroup of SM patients with aberrant mast cell CD2 expression, which warrants further investigation. In conclusion, we found no evidence of global increase in neutrophil extracellular trap release in SM.

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“…The limited number of proteomic studies performed in the field of mastocytosis individuated pro-inflammatory factors as novel potential blood biomarkers for systemic mastocytosis (SM) [26] and proinflammatory mechanisms possibly involved in pathogenesis of mastocytosis, as the upregulation of the signaling pathways downstream of Toll-like receptor 4, TNF-a, and IFN-g [27]. An interesting approach coupling plasma proteomics with single-cell transcriptomic analysis in SM patients and healthy subjects identified some cytokines and interleukins as specific biomarkers [28]. In a previous proteomics study, performed using a top-down platform, we highlighted the presence in saliva of peripheral and non-invasive candidate biomarkers of mastocytosis, some of them able to distinguish subtypes of SM with and without cutaneous symptoms (SM+C and SM−C), such as the R 26 variant of cystatin D [13].…”

Section: Discussionmentioning

confidence: 99%

Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study

Serrao,

Contini,

Guadalupi

et al. 2023

IJMS

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Mastocytosis, a rare blood disorder characterized by the proliferation of clonal abnormal mast cells, has a variegated clinical spectrum and diagnosis is often difficult and delayed. Recently we proposed the cathepsin inhibitor cystatin D-R26 as a salivary candidate biomarker of systemic mastocytosis (SM). Its C26 variant is able to form multiprotein complexes (mPCs) and since protein–protein interactions (PPIs) are crucial for studying disease pathogenesis, potential markers, and therapeutic targets, we aimed to define the protein composition of the salivary cystatin D-C26 interactome associated with SM. An exploratory affinity purification-mass spectrometry method was applied on pooled salivary samples from SM patients, SM patient subgroups with and without cutaneous symptoms (SM+C and SM−C), and healthy controls (Ctrls). Interactors specifically detected in Ctrls were found to be implicated in networks associated with cell and tissue homeostasis, innate system, endopeptidase regulation, and antimicrobial protection. Interactors distinctive of SM−C patients participate to PPI networks related to glucose metabolism, protein S-nitrosylation, antibacterial humoral response, and neutrophil degranulation, while interactors specific to SM+C were mainly associated with epithelial and keratinocyte differentiation, cytoskeleton rearrangement, and immune response pathways. Proteins sensitive to redox changes, as well as proteins with immunomodulatory properties and activating mast cells, were identified in patients; many of them were involved directly in cytoskeleton rearrangement, a process crucial for mast cell activation. Although preliminary, these results demonstrate that PPI alterations of the cystatin D-C26 interactome are associated with SM and provide a basis for future investigations based on quantitative proteomic analysis and immune validation.

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Proteomic and transcriptomic screening demonstrates increased mast cell–derived CCL23 in systemic mastocytosis

Cited by 6 publications

References 34 publications

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis

Exploring the casual association between gut microbiome, circulating inflammatory cytokines and chronic pancreatitis: A Mendelian randomization analysis

No indication of aberrant neutrophil extracellular trap release in indolent or advanced systemic mastocytosis

Salivary Cystatin D Interactome in Patients with Systemic Mastocytosis: An Exploratory Study

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