May 2024
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14 Reads
The American Journal of Human Genetics
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May 2024
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14 Reads
The American Journal of Human Genetics
April 2024
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50 Reads
Nature Communications
Coordinated cell interactions within the esophagus maintain homeostasis, and disruption can lead to eosinophilic esophagitis (EoE), a chronic inflammatory disease with poorly understood pathogenesis. We profile 421,312 individual cells from the esophageal mucosa of 7 healthy and 15 EoE participants, revealing 60 cell subsets and functional alterations in cell states, compositions, and interactions that highlight previously unclear features of EoE. Active disease displays enrichment of ALOX15⁺ macrophages, PRDM16⁺ dendritic cells expressing the EoE risk gene ATP10A, and cycling mast cells, with concomitant reduction of TH17 cells. Ligand–receptor expression uncovers eosinophil recruitment programs, increased fibroblast interactions in disease, and IL-9⁺IL-4⁺IL-13⁺ TH2 and endothelial cells as potential mast cell interactors. Resolution of inflammation-associated signatures includes mast and CD4⁺ TRM cell contraction and cell type-specific downregulation of eosinophil chemoattractant, growth, and survival factors. These cellular alterations in EoE and remission advance our understanding of eosinophilic inflammation and opportunities for therapeutic intervention.
March 2024
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23 Reads
Cell Reports
December 2023
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68 Reads
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3 Citations
Proceedings of the National Academy of Sciences
The salt-inducible kinases (SIK) 1–3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.
December 2023
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37 Reads
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2 Citations
Immunity
October 2023
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92 Reads
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1 Citation
In metagenomics, the pool of uncharacterized microbial enzymes presents a challenge for functional annotation. Among these, carbohydrate-active enzymes (CAZymes) stand out due to their pivotal roles in various biological processes related to host health and nutrition. Here, we present CAZyLingua, the first tool that harnesses protein language model embeddings to build a deep learning framework that facilitates the annotation of CAZymes in metagenomic datasets. Our benchmarking results showed on average a higher F1 score (reflecting an average of precision and recall) on the annotated genomes of Bacteroides thetaiotaomicron, Eggerthella lenta and Ruminococcus gnavus compared to the traditional sequence homology-based method in dbCAN2. We applied our tool to a paired mother/infant longitudinal dataset and revealed unannotated CAZymes linked to microbial development during infancy. When applied to metagenomic datasets derived from patients affected by fibrosis-prone diseases such as Crohn's disease and IgG4-related disease, CAZyLingua uncovered CAZymes associated with disease and healthy states. In each of these metagenomic catalogs, CAZyLingua discovered new annotations that were previously overlooked by traditional sequence homology tools. Overall, the deep learning model CAZyLingua can be applied in combination with existing tools to unravel intricate CAZyme evolutionary profiles and patterns, contributing to a more comprehensive understanding of microbial metabolic dynamics.
October 2023
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54 Reads
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1 Citation
Science Translational Medicine
Effective tissue repair requires coordinated intercellular communication to sense damage, remodel the tissue, and restore function. Here, we dissected the healing response in the intestinal mucosa by mapping intercellular communication at single-cell resolution and integrating with spatial transcriptomics. We demonstrated that a risk variant for Crohn’s disease, hepatocyte growth factor activator (HGFAC) Arg ⁵⁰⁹ His (R509H), disrupted a damage-sensing pathway connecting the coagulation cascade to growth factors that drive the differentiation of wound-associated epithelial (WAE) cells and production of a localized retinoic acid (RA) gradient to promote fibroblast-mediated tissue remodeling. Specifically, we showed that HGFAC R509H was activated by thrombin protease activity but exhibited impaired proteolytic activation of the growth factor macrophage-stimulating protein (MSP). In Hgfac R509H mice, reduced MSP activation in response to wounding of the colon resulted in impaired WAE cell induction and delayed healing. Through integration of single-cell transcriptomics and spatial transcriptomics, we demonstrated that WAE cells generated RA in a spatially restricted region of the wound site and that mucosal fibroblasts responded to this signal by producing extracellular matrix and growth factors. We further dissected this WAE cell–fibroblast signaling circuit in vitro using a genetically tractable organoid coculture model. Collectively, these studies exploited a genetic perturbation associated with human disease to disrupt a fundamental biological process and then reconstructed a spatially resolved mechanistic model of tissue healing.
October 2023
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13 Reads
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7 Citations
Journal of the American Chemical Society
An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified Muribaculum intestinale as one of only two members with an oversized effect on T-cell populations. Here we report the identification and characterization of a lipid, MiCL-1, as the responsible metabolite. MiCL-1 is an 18:1-16:0 cardiolipin, whose close relatives are found on concave lipid surfaces of both mammals and bacteria. MiCL-1 was synthesized to confirm the structural analysis and functionally characterized in cell-based assays. It has a highly restrictive structure–activity profile, as its chain-switched analog fails to induce responses in any of our assays. MiCL-1 robustly induces the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-23, but has no detectable effect on the anti-inflammatory cytokine IL-10. As is the case with other recently discovered immunomodulatory lipids, MiCL-1 requires functional TLR2 and TLR1 but not TLR6 in cell-based assays.
September 2023
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23 Reads
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5 Citations
Journal of the American Chemical Society
Coley’s toxins, an early and enigmatic form of cancer (immuno)therapy, were based on preparations of Streptococcus pyogenes. As part of a program to explore bacterial metabolites with immunomodulatory potential, S. pyogenes metabolites were assayed in a cell-based immune assay, and a single membrane lipid, 18:1/18:0/18:1/18:0 cardiolipin, was identified. Its activity was profiled in additional cellular assays, which showed it to be an agonist of a TLR2–TLR1 signaling pathway with a 6 μM EC50 and robust TNF-α induction. A synthetic analog with switched acyl chains had no measurable activity in immune assays. The identification of a single immunogenic cardiolipin with a restricted structure–activity profile has implications for immune regulation, cancer immunotherapy, and poststreptococcal autoimmune diseases.
June 2023
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68 Reads
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7 Citations
Cell Reports
Autophagy is an essential cellular process that is deeply integrated with innate immune signaling; however, studies that examine the impact of autophagic modulation in the context of inflammatory conditions are lacking. Here, using mice with a constitutively active variant of the autophagy gene Beclin1, we show that increased autophagy dampens cytokine production during a model of macrophage activation syndrome and in adherent-invasive Escherichia coli (AIEC) infection. Moreover, loss of functional autophagy through conditional deletion of Beclin1 in myeloid cells significantly enhances innate immunity in these contexts. We further analyzed primary macrophages from these animals with a combination of transcriptomics and proteomics to identify mechanistic targets downstream of autophagy. Our study reveals glutamine/glutathione metabolism and the RNF128/TBK1 axis as independent regulators of inflammation. Altogether, our work highlights increased autophagic flux as a potential approach to reduce inflammation and defines independent mechanistic cascades involved in this control.
... Additionally, at 2 h post-infection, we noted up-regulation in genes that modulate the inflammatory response, such as Dual-Specificity [26], including G protein-coupled receptor 35 (Gpr35), involved in modulating inflammatory responses [27] and Salt inducible Kinase 1 (SIK1) [28], crucial for balancing pro-and anti-inflammatory cytokine responses during innate immune activation. Both Grp35 and SIK1 are upregulated about 2.6-fold at 6 h post-infection, likely as a result of DUSP2 stimulation. ...
December 2023
Proceedings of the National Academy of Sciences
... T h 17 cells, identified by IL17Apositive cells, harbored significant enrichment (Fig 1A) of IBD gene expressions in adult CD and a suggestive significance (raw P = 0.008; false discovery rate [FDR] = 0.12) in pediatric CD. T h 1 cells were not identified in the adult sample of Kong et al's study (25). The association of ILC3 (type 3 innate lymphoid) cells in pediatric did not present in adult CD, which could be attributed to the fact that ILC cells play a role in the initial phase of the disease (26). ...
December 2023
Immunity
... In this research, the changes of gut microorganisms caused by AP were greatly influenced by TFC. Muribaculum intestinale was reported to induce adaptive immune responses during homeostasis, and was greatly increased after AP induction [23]. However, TFC significantly reduced the level of Muribaculum intestinale. ...
October 2023
Journal of the American Chemical Society
... This challenge becomes especially pressing when it comes to lipids of microbial origin as these often possess previously undiscovered structural modifications and highly specific structure-activity profiles [12][13][14] for which authentic standards are most often not readily available. [15][16][17] In recent years it became evident that halocapnines [18] and bacterial sulfonolipids ( Figure 1A) are not only of importance for bacterial physiology, [19] but also take part in different host-microbe interactions. Specifically, sulfonosphingolipids known as RIFs [20,21] and sulfonolipid IOR-1A, [22,23] which belong to the prokaryotic counterparts of the sphingolipid class, [24] play a role in regulating cell differentiation processes in the single-celled eukaryote Salpingoeca rosetta. ...
September 2023
Journal of the American Chemical Society
... Here, we demonstrated that YTHDC1 knockdown inhibited Beclin1 and LC3II protein expression and further promoted p62 protein levels under LPS/ IFN-γ treatment in vitro, suggesting that YTHDC1 is involved in autophagy regulation in the inflammatory microenvironment. A recent study revealed that Beclin1deficient BMDMs exhibited increased levels of phosphorylated NF-κB p65 [31]. In accordance with this, our work indicated the significance of YTHDC1 in regulating NF-κB signaling through Beclin1-dependent autophagy. ...
June 2023
Cell Reports
... The resulting peptides are then loaded onto HLA-I molecules by the peptide loading complex within the endoplasmic reticulum (60). HLA-II molecules are exclusively expressed on professional antigen-presenting cells, such as dendritic cells, B cells, and macrophages, and bind longer peptides ranging between 12 and 30 amino acids in length (61,62). These peptides derive from extracellular proteins, which can be either harmless or associated with pathogens. ...
June 2023
Immunity
... A recent study revealed that GPR156 modulates lipid droplet dynamics in infected macrophages lacking membrane magnesium transporter 1 (ref. 28). It may be worth examining whether phospholipid-mediated activation of GPR156 has any correlation with its role in lipid droplet stabilization. ...
June 2023
Cell Host & Microbe
... This interaction is distinguished by molecular signals, biochemical communication, and a nuanced equilibrium of microbial communities, all of which have substantial implications for our well-being (3) (4). While some microorganisms are beneficial, playing crucial roles in processes such as digestion and immune system priming, others with pathogenic properties can lead to diseases and infections (5) (6). Previous studies, such as the Human Microbiome Project (HMP), have provided insights into the human microbiome in terms of human health and diseases. ...
May 2023
Trends in Immunology
... CD4+ T cells can induce inflammation and maintain inflammation in the mucosa by producing pro-inflammatory cytokines IL-12, IL-21, and IL-23, playing an important role in CD [28]. The dysregulation of the immune response is closely related to genetic factors that predispose to CD [29]. ...
January 2023
Immunity
... BG treatment effectively mitigated this imbalance by reducing the conversion of Tregs to Th17 cells. Elevated local and serum IL-17 levels in CD patients underscored the significance of IL-17 + T cells in disease severity (Pedersen et al. 2022). BG treatment increased anti-inflammatory factors such as IL-10, IL-5, Foxp3, and GATA3 in the colon, indicative of enhanced anti-inflammatory responses. ...
September 2022
Immunity