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Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study

ABSTRACT: Haptoglobin (Hp) scavenges cell-free hemoglobin and correlates with the prognosis of human sepsis, a life-threatening systemic inflammatory condition. Despite extensive research on Hp glycosylation as a glyco-biomarker for cancers, understanding glycosylated modifications of Hp in sepsis patients (SPs) remains limited. Our study reveals elevated levels of terminal fucosylation at Asn207 and Asn211 of Hp in SP plasma, along with heightened inflammatory responses, compared to healthy controls (trial registration NCT05911711). Fucosylated (Fu)-Hp purified from SPs upregulates inflammatory cytokines and chemokines, along with NLRP3 inflammasome activation. Single-cell RNA sequencing identifies a distinct macrophage-like cell population with increased expressions of inflammatory mediators and FUT4 in response to Fu-Hp. Additionally, Mincle, a C-type lectin receptor, interacts with Fu-Hp to amplify the inflammatory responses and signaling. Moreover, the Hp fucosylation (AAL) level significantly correlates with the levels of inflammatory cytokines in sepsis patients, suggesting that Fu-Hp is clinically relevant. Finally, Fu-Hp treatment significantly enhances the levels of inflammatory cytokines in the plasma and various tissues of mice. Together, our findings reveal a previously unrecognized role of Fu-Hp, derived from sepsis patients, in driving inflammation, and suggest that targeting Fu-Hp could serve as a promising intervention for combating sepsis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270838 | GEO | 2025/01/15

REPOSITORIES: GEO

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Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study

Project description:Haptoglobin (Hp) scavenges cell-free hemoglobin and correlates with the prognosis of human sepsis, a life-threatening systemic inflammatory condition. Despite extensive research on Hp glycosylation as a glyco-biomarker for cancers, understanding glycosylated modifications of Hp in sepsis patients (SPs) remains limited. Our study reveals elevated levels of terminal fucosylation at Asn207 and Asn211 of Hp in SP plasma, along with heightened inflammatory responses, compared to healthy controls (trial registration NCT05911711). Fucosylated (Fu)-Hp purified from SPs upregulates inflammatory cytokines and chemokines, along with NLRP3 inflammasome activation. Single-cell RNA sequencing identifies a distinct macrophage-like cell population with increased expressions of inflammatory mediators and FUT4 in response to Fu-Hp. Additionally, Mincle, a C-type lectin receptor, interacts with Fu-Hp to amplify the inflammatory responses and signaling. Moreover, the Hp fucosylation (AAL) level significantly correlates with the levels of inflammatory cytokines in sepsis patients, suggesting that Fu-Hp is clinically relevant. Finally, Fu-Hp treatment significantly enhances the levels of inflammatory cytokines in the plasma and various tissues of mice. Together, our findings reveal a previously unrecognized role of Fu-Hp, derived from sepsis patients, in driving inflammation, and suggest that targeting Fu-Hp could serve as a promising intervention for combating sepsis.

2025-01-15 | GSE286141 | GEO

Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study [scRNAseq_Sepsis]

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Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study [scRNAseq_Fu-Hp]

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Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study [scRNAseq_Fu-Hp]

Project description:Fucosylated haptoglobin drives inflammation via Mincle in sepsis: an observational study [scRNAseq_Fu-Hp]

| PRJNA1210551 | ENA

Transcriptome analysis of blood monocytes from sepsis patients

Project description:Blood monocytes serve as the first line of host defense and are equipped to recognize and respond to infection by triggering an immune-inflammatory response. While most information on these cells comes from in vitro studies in humans or in vivo studies in mice, little is known about monocytes under human disease conditions. We investigated the role of monocytes during sepsis and its resolution in humans. A transcriptomal and functional analysis of blood monocytes from patients during gram negative sepsis and at recovery was performed. Monocytes from sepsis patients showed upregulation of a large number of pro-inflammatory genes and cytokines/chemokines, consistent with an ongoing systemic inflammation. However, these cells showed impairment to ex vivo endotoxin (LPS) challenge, displaying a quantitative decrease in the number of LPS-inducible genes. Moreover, they downregulated the expression of several pro-inflammatory cytokine/chemokine genes, activation marker genes and transcription factors associated with monocyte/macrophage activation, upon ex vivo LPS stimulation. Functionally, they downregulated expression of inflammatory cytokines/chemokines and antigen presentation-related molecules and functions. In contrast, genes and functions related to phagocytosis, anti-microbial activity and tissue remodeling where remained unaffected or even enhanced . Collectively, our observations suggest a genetic and functional re-programming of these cells during human sepsis progression. Understanding the molecular mechanisms which regulate this re-programming will allow to devise strategies which could modulate the response of these cells and hence, disease progression. Blood monocytes from gram-negative sepsis patients during sepsis (Sepsis) and following their recovery (Recovery/Basal) as well as healthy donor (control) were isolated. Thereafter, these cells were treated ex vivo with or without LPS for 3h and analysed for transcriptomic study.

2014-05-14 | E-GEOD-46955 | biostudies-arrayexpress

Induction of stable human FOXP3+ Tregs by a parasite-derived TGF-β mimic

Project description:Objectives. Immune homeostasis in the intestinal tract is tightly controlled by FOXP3+ regulatory T cells (Tregs), with loss of this Treg-mediated control linked to development of chronic conditions, such as inflammatory bowel disease (IBD). As a mechanism of immune evasion, several species of intestinal parasites strengthen intestinal Treg activity, leading to the notion that parasite-derived products could be harnessed and used as an immunoregulatory therapy for IBD. It has been previously demonstrated that the parasite Heligmosomoides polygyrus secretes a molecule (Hp-TGM) which mimics the ability of TGF-β to induce FOXP3 expression in CD4+ T cells. Our aim was to investigate whether Hp-TGM could induce human FOXP3+ Tregs as a potential therapeutic approach. Methods. Human CD4+ T cells from healthy volunteers were expanded in the presence of Hp-TGM or mammalian TGF-β. The induction of Tregs was measured by flow cytometric detection of FOXP3 and other Treg markers, such as CTLA-4 and CD25. Epigenetic changes were detected using ChIP-Seq and pyrosequencing of FOXP3. Treg phenotype stability was assessed following inflammatory cytokine challenge and Treg function was assessed by cellular co-culture suppression assays and secreted cytokines measured by cytometric bead array. Results. Hp-TGM efficiently induced FOXP3 expression (>60%), in addition to another Treg functional marker CTLA-4. Hp-TGM caused epigenetic modification of the FOXP3 loci to a greater extent than did TGF-β. Hp-TGM-induced Tregs also had superior suppressive function compared to TGF--induced Tregs, and retained their phenotype following exposure to inflammatory cytokines. Hp-TGM also induced a Treg phenotype in in vivo differentiated Th17 cells, indicating its potential to re-program memory cells to enhance immune tolerance. Conclusion. These data indicate Hp-TGM has the potential to be used to generate stable human FOXP3+ Tregs to treat IBD.

2021-04-29 | GSE164548 | GEO

Trichuris suis soluble products induce Rab7b expression and limit TLR4 responses in human dendritic cells

Project description:Inflammatory immune disorders such as inflammatory bowel disease (IBD) and multiple sclerosis (MS) are major health problems. Currently, the intestinal whipworm Trichuris suis is being explored in clinical trials to reduce inflammation in these diseases, however, the mechanisms by which the parasite affects the host immune system are not known. Here we determined the effects of T. suis soluble products (SPs) on toll-like receptor-4 (TLR4)-stimulated human dendritic cells (DCs) using Illumina bead chip gene arrays. Pathway analysis of lipopolysaccharide (LPS)-stimulated DCs with or without T. suis treatment showed that costimulation with T. suis SPs resulted in a down-regulation of both the myeloid differentiation primary response gene 88 (MyD88)-dependent and the TIR-domain-containing adaptor-inducing interferon-β (TRIF)-dependent signalling pathways triggered by TLR4. These data were verified using quantitative real-time PCR of several key genes within these pathways and/or defining their protein levels. In addition, T. suis SPs induce Rab7b, a negative regulator of TLR4 signalling that interferes with its trafficking, which coincided with a reduced surface expression of TLR4. These data indicate that the mechanism by which T. suis SPs reduce inflammatory responses is through suppression of both TLR4 signalling and surface expression on DCs.

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Comparative Proteomic Analysis of Fucosylated Glycoproteins in Bacteroides thetaiotaomicron under Different Polysaccharide Nutrition Conditions

Project description:Bacteroides thetaiotaomicron, one of the most eminent representative gut commensal Bacteroides species, is able to use the L-fucose in host-derived and dietary polysaccharides to modify its capsular polysaccharides and glycoproteins through a mammalian-like salvage metabolic pathway. This process is essential for the colonization of the bacteria and for symbiosis with the host. However, despite the importance of fucosylated proteins (FGPs) in Bacteroide thetaiotaomicron, their types, distribution, and functions remain unclear. In this project, the effects of different saccharide (glucose, corn starch, mucin, and fucoidan) nutrition conditions on FGP expressions and fucosylation are investigated using a chemical biological method based on metabolic labeling and bioorthogonal reaction. According to the results of label-free quantification, 559 FGPs (205 downregulated and 354 upregulated) are affected by the dietary conditions. Of these differentially expressed proteins, 65 proteins show extremely sensitive fucosylation levels. Specifically, the fucosylation of the chondroitin sulfate ABC enzyme, Sus proteins, and cationic efflux system proteins varies significantly upon the addition of mucin, corn starch, or fucoidan. Moreover, these polysaccharides can trigger an appreciable increase in the fucosylation level of the two-component system and ammonium transport proteins. These results highlight the efficiency of the combined metabolic glycan labeling and bio-orthogonal reaction in enriching the intestinal Bacteroide glycoproteins. Moreover, it emphasize the sensitivity of Bacteroides fucosylation to polysaccharide nutrition conditions, which allows for the regulation of bacterial growth.

2022-02-08 | PXD023756 | Pride

High titers and low fucosylation of early anti-SARS-CoV-2 IgG promote hyper-inflammation by anti-inflammatory macrophages (MIL10)

Project description:Patients diagnosed with coronavirus disease 2019 (COVID-19) mostly become critically ill around the time of activation of the adaptive immune response. Here, we provide evidence that antibodies play a role in the worsening of disease at the time of seroconversion. We show that early phase severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) spike protein-specific IgG in serum of critically ill COVID-19 patients induces hyper-inflammatory responses by human alveolar macrophages. We identified that this excessive inflammatory response is dependent on two antibody features that are specific for patients with severe COVID-19. First, inflammation is driven by high titers of anti-spike IgG, a hallmark of severe disease. Second, we found that anti-spike IgG from patients with severe COVID-19 is intrinsically more pro-inflammatory because of different glycosylation, particularly low fucosylation, of the Fc tail. Notably, low anti-spike IgG fucosylation normalized in a few weeks after initial infection with SARS-CoV-2, indicating that the increased antibody-dependent inflammation mainly occurs at the time of seroconversion. We identified Fcγ Receptor (FcγR) IIa and FcγRIII as the two primary IgG receptors that are responsible for the induction of key COVID-19-associated cytokines such as interleukin-6 and tumor necrosis factor. In addition, we show that anti-spike IgG-activated macrophages can subsequently break pulmonary endothelial barrier integrity and induce microvascular thrombosis in vitro. Finally, we demonstrate that the hyper-inflammatory response induced by anti-spike IgG can be specifically counteracted by fostamatinib, an FDA- and EMA-approved therapeutic small molecule inhibitor of the kinase, Syk.

2021-04-30 | E-MTAB-10431 | biostudies-arrayexpress

Proteomic analysis identified age-associated prognostic biomarkers in pneumonia-derived pediatric sepsis

Project description:Pediatric sepsis is a leading cause of mortality in children across the world. Within pediatric sepsis, how developmental age-specific host immune response impact on the occurrence and development of pediatric sepsis is still unknown, especially between infants and toddlers, which were the major susceptible age groups in sepsis. Experimental design In this study, we applied a nested case-control study strategy and analyzed the plasma proteomes of pediatric sepsis patients between infants and toddlers in comparison to their age-matched controls respectively. Each age group consists of three subgroups with different outcomes. One hundred and ten plasma samples were pooled into 16 samples for quantitative identification by LC-MS/MS. Results It was totally quantified 677 proteins. In comparison to toddlers, infant sepsis patients were characteristic with dominant neutrophil-mediated defense, suppressed adaptive immunity and NK-mediated cytotoxicity. Besides, pentose phosphate pathway was more up-regulated in infants and associated with poor outcome. Moreover, combined Hp and Thbs1 with the AUC value of 0.958 (95%CI, 0.868, 1.000) was confirmed as potential infant-adapted prognostic marker of poor outcome in sepsis. Conclusion and clinical relevance Our proteomic analysis of age-associated pediatric sepsis combined with clinical laboratory data provided a comprehensive insight into the complex, multifactorial heterogeneous host response to pediatric sepsis and allowed identification of critical differences between infant and toddler sepsis. Moreover, we confirmed that combined Hp and Thbs1 is more infant-adapted and serves as a potential prognostic biomarker for poor outcome of infant sepsis, promoting the application of age-adapted precision medicine in pediatric sepsis.

2021-11-01 | PXD026656 | Pride

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