Evaluation of the relationship between the spleen volume and the disease activity in ulcerative colitis and Crohn disease

Kawashima, Kazumasa; Onizawa, Michio; Fujiwara, Tatsuo; Gunji, Naohiko; Imamura, Hidemichi; Katakura, Kyoko; Ohira, Hiromasa

doi:10.1097/md.0000000000028515

Cited by 17 publications

(11 citation statements)

References 26 publications

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“…This stress can trigger EMH, in which hematopoietic stem cells are mobilized to sites outside the bone marrow, the primary site for adult hematopoiesis, to expand hematopoiesis often in the spleen [43,[45][46][47]. Splenic EMH occurs with enlarged spleens, which are observed both in mice subjected to the experimental colitis model and in patients with Crohn's disease [43,48]. The splenic EMH often skews toward myelopoiesis, leading to excessive production of myeloid cells including neutrophils [49].…”

Section: Discussionmentioning

confidence: 99%

“…Chronic inflammation, including chronic intestinal inflammation, causes hematopoietic stress. This stress can trigger EMH, in which hematopoietic stem cells are mobilized to sites outside the bone marrow, the primary site for adult hematopoiesis, to expand hematopoiesis often in the spleen [43,[45][46][47]. Splenic EMH occurs with enlarged spleens, which are observed both in mice subjected to the experimental colitis model and in patients with Crohn's disease [43,48].…”

Section: Discussionmentioning

confidence: 99%

“…Neutrophils are known to possess plasticity in their transcriptome, proteome, and function [43, 44]. The distinct transcriptomic and proteomic profiles of neutrophils produced in the absence of WNT5 from those in the presence of WNT5 or even PMN-MDSCs from tumor-bearing mice further demonstrate the high plasticity of this class of immune cells.…”

Section: Discussionmentioning

confidence: 99%

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Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Luan

Wang

et al. 2023

Preprint

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WNT5A and WNT5B are two close homologs, both of which are implicated in the pathogenesis of inflammatory bowel diseases. However, the roles these two proteins play in the disease remain largely uncharacterized. Here, we report that double knockout of Wnt5a and Wnt5b (Wnt5 DKO) protects mice from Dextran Sodium Sulfate (DSS)-induced colitis in mice, accompanied with greater splenomegaly, stronger expansion of peripheral myeloid cells, and less colonic CD8+ T cell granzyme B expression than those of the control mice. Depletion of neutrophils or splenectomy abrogates the phenotypic differences between Wnt5 DKO and control mice largely by exacerbating colitis phenotypes and increasing colonic CD8+ T cell GZMB expression in the Wnt5 DKO mice. In addition, neutrophils from the Wnt5 DKO colitic mice exert stronger suppression of CD8+ T cells than those from the control mice in culture. Single-cell RNA sequencing and proteomic analyses indicate that neutrophils from DSS-treated Wnt5 DKO mice are of hyper-immunosuppressive and hypo-inflammatory characteristics and are distinct from those of DSS-treated control mice as well as myeloid-derived suppressor cells in tumor-bearing mice. Thus, our study reveals that the lack of WNT5 reprograms neutrophils in spleens to limit colonic injury during DSS-induced colitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Luan

Wang

et al. 2023

Preprint

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“…SIMs-treated mice were also protected from DSS-induced colon shortening (Figure 4c,d). Since IBD patients often experience splenomegaly, a decrease in spleen weight to end bodyweight ratio is an indicator of effectively moderating the adverse immune response associated with IBD; 46 mice treated with SIMs presented with a lower ratio (Figure 4e). As with splenomegaly, shortening of the colon is often associated with ulcerative colitis, and the suppression of colon shortening and reduced splenomegaly is observed in mice treated with SIMs.…”

Section: Therapeutic Efficacy Of Sims In Dss-induced Acute Colitis In...mentioning

confidence: 99%

Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles

Uthaman,

Parvinroo,

Mathew

et al. 2024

ACS Nano

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Ulcerative colitis is a chronic condition in which a dysregulated immune response contributes to the acute intestinal inflammation of the colon. Current clinical therapies often exhibit limited efficacy and undesirable side effects. Here, programmable nanomicelles were designed for colitis treatment and loaded with RU.521, an inhibitor of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. STING-inhibiting micelles (SIMs) comprise hyaluronic acid-stearic acid conjugates and include a reactive oxygen species (ROS)-responsive thioketal linker. SIMs were designed to selectively accumulate at the site of inflammation and trigger drug release in the presence of ROS. Our in vitro studies in macrophages and in vivo studies in a murine model of colitis demonstrated that SIMs leverage HA-CD44 binding to target sites of inflammation. Oral delivery of SIMs to mice in both preventive and delayed therapeutic models ameliorated colitis's severity by reducing STING expression, suppressing the secretion of proinflammatory cytokines, enabling bodyweight recovery, protecting mice from colon shortening, and restoring colonic epithelium. In vivo end points combined with metabolomics identified key metabolites with a therapeutic role in reducing intestinal and mucosal inflammation. Our findings highlight the significance of programmable delivery platforms that downregulate inflammatory pathways at the intestinal mucosa for managing inflammatory bowel diseases.

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“…Beside blood, some other tissues are also known to have important roles in certain traits, including spleen on IBD (Kawashima et al, 2022), lung on HT (HEPPER et al, 1960) and CAD (Gunnell et al, 2003), ovary on BC (Claus et al, 1996), liver on lipids (Arvind et al, 2019), brain on SCZ , and fat on lipids and T2D (Richard et al, 2020;Gaynor et al, 2022). For those tissues, their tissue-specific annotations were selected in the corresponding traits by the forward stagewise selection algorithm.…”

Section: Selected Functional Annotationsmentioning

confidence: 99%

Estimating genetic architecture and integrating functional annotations improve polygenic risk scores derived from GWAS summary statistics

Zhao,

Jiang,

Girgenti

2023

Preprint

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Constructing accurate polygenic risk scores (PRS) can benefit the prevention and early treatment of complex diseases. This can be accomplished by leveraging different information characterizing the effects of genetic variants on the diseases, and incorporating functional annotations. In this article, we propose a Genome-Wide Empirical Bayes (GWEB) method to first estimate the genetic architecture with the consideration of linkage disequilibrium (LD) among the genetic variants, and utilize the estimates to improve PRS derived from GWAS summary statistics. Our method further incorporates functional annotations to improve prediction accuracy. No parameters need to be tuned with other individual-level GWAS data. Extensive simulations showed that GWEB outperformed existing methods in different genetic architecture scenarios. Real data applications on six quantitative traits and six binary diseases demonstrated that, without functional annotations, GWEB can achieve 0.1-24% (average: 7%) relative improvement in terms of predictive r2 over the best performance of seven existing methods. Moreover, compared to the existing method using annotation information, GWEB can achieve 3-58% (average: 12%) relative improvement after integrating 120 functional annotations. The prediction model can be built within 1.2h and 40G memory after parallelized on 22 Intel Xeon cores.

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Evaluation of the relationship between the spleen volume and the disease activity in ulcerative colitis and Crohn disease

Cited by 17 publications

References 26 publications

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Loss of WNT5 Proteins Reprograms Neutrophils in the Spleen to Provide Protection for DSS-Induced Colitis

Inhibiting the cGAS-STING Pathway in Ulcerative Colitis with Programmable Micelles

Estimating genetic architecture and integrating functional annotations improve polygenic risk scores derived from GWAS summary statistics

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