scholarly journals Macrophage development and activation involve coordinated intron retention in key inflammatory regulators

2020 ◽  
Vol 48 (12) ◽  
pp. 6513-6529 ◽  
Author(s):  
Immanuel D Green ◽  
Natalia Pinello ◽  
Renhua Song ◽  
Quintin Lee ◽  
James M Halstead ◽  
...  
Keyword(s):  
Intron Retention ◽  
Innate Immune ◽  
Cdna Sequencing ◽  
Proteomics Analysis ◽  
Expression Of Genes ◽  
Essential Components ◽  
Genes Encoding ◽  
Monocytes And Macrophages ◽  
And Function ◽  
Inflammatory Signalling

Abstract Monocytes and macrophages are essential components of the innate immune system. Herein, we report that intron retention (IR) plays an important role in the development and function of these cells. Using Illumina mRNA sequencing, Nanopore direct cDNA sequencing and proteomics analysis, we identify IR events that affect the expression of key genes/proteins involved in macrophage development and function. We demonstrate that decreased IR in nuclear-detained mRNA is coupled with increased expression of genes encoding regulators of macrophage transcription, phagocytosis and inflammatory signalling, including ID2, IRF7, ENG and LAT. We further show that this dynamic IR program persists during the polarisation of resting macrophages into activated macrophages. In the presence of proinflammatory stimuli, intron-retaining CXCL2 and NFKBIZ transcripts are rapidly spliced, enabling timely expression of these key inflammatory regulators by macrophages. Our study provides novel insights into the molecular factors controlling vital regulators of the innate immune response.

scholarly journals SlpB Protein Enhances the Probiotic Potential of L. lactis NCDO 2118 in Colitis Mice Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Giovanna A. Belo ◽  
Bárbara F. Cordeiro ◽  
Emiliano R. Oliveira ◽  
Marina P. Braga ◽  
Sara H. da Silva ◽  
...  
Keyword(s):  
Weight Loss ◽  
Activity Index ◽  
Disease Activity Index ◽  
Fermented Food ◽  
Mice Model ◽  
Probiotic Potential ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Bowel Diseases ◽  
And Function

Bacteria used in the production of fermented food products have been investigated for their potential role as modulators of inflammation in gastrointestinal tract disorders such as inflammatory bowel diseases (IBD) that cause irreversible changes in the structure and function of gut tissues. Ulcerative colitis (UC) is the most prevalent IBD in the population of Western countries, and it is marked by symptoms such as weight loss, rectal bleeding, diarrhea, shortening of the colon, and destruction of the epithelial layer. The strain Propionibacterium freudenreichii CIRM-BIA 129 recently revealed promising immunomodulatory properties that greatly rely on surface-layer proteins (Slp), notably SlpB. We, thus, cloned the sequence encoding the SlpB protein into the pXIES-SEC expression and secretion vector, and expressed the propionibacterial protein in the lactic acid bacterium Lactococcus lactis NCDO 2118. The probiotic potential of L. lactis NCDO 2118 harboring pXIES-SEC:slpB (L. lactis-SlpB) was evaluated in a UC-mice model induced by Dextran Sulfate Sodium (DSS). During colitis induction, mice receiving L. lactis-SlpB exhibited reduced severity of colitis, with lower weight loss, lower disease activity index, limited shortening of the colon length, and reduced histopathological score, with significant differences, compared with the DSS group and the group treated with L. lactis NCDO 2118 wild-type strain. Moreover, L. lactis-SlpB administration increased the expression of genes encoding tight junction proteins zo-1, cln-1, cln-5, ocln, and muc-2 in the colon, increased IL-10 and TGF-β, and decreased IL-17, TNF-α, and IL-12 cytokines in the colon. Therefore, this work demonstrates that SlpB recombinant protein is able to increase the probiotic potential of the L. lactis strain to alleviate DSS-induced colitis in mice. This opens perspectives for the development of new approaches to enhance the probiotic potential of strains by the addition of SlpB protein.

scholarly journals Sex-Dimorphic Behavioral Alterations and Altered Neurogenesis in U12 Intron Splicing-Defective Zrsr1 Mutant Mice

2019 ◽  
Vol 20 (14) ◽  
pp. 3543 ◽  
Author(s):  
Francisco Alén ◽  
Isabel Gómez-Redondo ◽  
Patricia Rivera ◽  
Juan Suárez ◽  
Priscila Ramos-Ibeas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intron Retention ◽  
Mutant Mice ◽  
Behavioral Alterations ◽  
Altered Expression ◽  
Cell Network ◽  
Expression Of Genes ◽  
Adult Cell ◽  
Controlling Behavior ◽  
And Function

Mutant mice with respect to the splicing factor Zrsr1 present altered spermatogenesis and infertility. To investigate whether Zrsr1 is involved in the homeostatic control that the hypothalamus exerts over reproductive functions, we first analyzed both differential gene and isoform expression and alternative splicing alterations in Zrsr1 mutant (Zrsr1mu) hypothalamus; second, we analyzed the spontaneous and social behavior of Zrsr1mu mice; and third, we analyzed adult cell proliferation and survival in the Zrsr1mu hypothalamus. The Zrsr1mu hypothalamus showed altered expression of genes and isoforms related to the glutathione metabolic process, synaptonemal complex assembly, mRNA transport, and altered splicing events involving the enrichment of U12-type intron retention (IR). Furthermore, increased IR in U12-containing genes related with the prolactin, progesterone, and gonadotropin-releasing hormone (GnRH) reproductive signaling pathway was observed. This was associated with a hyperactive phenotype in both males and females, with an anxious phenotype in females, and with increased social interaction in males, instead of the classical aggressive behavior. In addition, Zrsr1mu females but not males exhibited reduced cell proliferation in both the hypothalamus and the subventricular zone. Overall, these results suggest that Zrsr1 expression and function are relevant to organization of the hypothalamic cell network controlling behavior.

scholarly journals ZBED1 Regulates Genes Important for Multiple Biological Processes of the Placenta

Genes ◽  
2022 ◽  
Vol 13 (1) ◽  
pp. 133
Author(s):  
Simone Johansen ◽  
Sofie Traynor ◽  
Malene Laage Ebstrup ◽  
Mikkel Green Terp ◽  
Christina Bøg Pedersen ◽  
...  
Keyword(s):  
Cell Model ◽  
Trophoblast Cell ◽  
Innate Immune ◽  
Bewo Cell ◽  
Biological Processes ◽  
Bewo Cells ◽  
Genes Encoding ◽  
And Function

The transcription factor ZBED1 is highly expressed in trophoblast cells, but its functions in the processes of trophoblast and placental biology remain elusive. Here, we characterized the role of ZBED1 in trophoblast cell differentiation using an in vitro BeWo cell model. We demonstrate that ZBED1 is enhanced in its expression early after forskolin-induced differentiation of BeWo cells and regulates many of the genes that are differentially expressed as an effect of forskolin treatment. Specifically, genes encoding markers for the differentiation of cytotrophoblast into syncytiotrophoblast and factors essential for trophoblast cell fusion and invasion were negatively regulated by ZBED1, indicating that ZBED1 might be important for maintaining a steady pool of cytotrophoblast cells. In addition, ZBED1 affected genes involved in the regulation of trophoblast cell survival and apoptosis, in agreement with the observed increase in apoptosis upon knockdown of ZBED1 in forskolin-treated BeWo cells. In addition, genes implicated in the differentiation, recruitment, and function of innate immune cells by the placenta were affected by ZBED1, further suggesting a role for this protein in the regulation of maternal immune tolerance. In conclusion, our study implicates ZBED1 in major biological processes of placental biology.

scholarly journals The WNT1G177C mutation specifically affects skeletal integrity in a mouse model of osteogenesis imperfecta type XV

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Nele Vollersen ◽  
Wenbo Zhao ◽  
Tim Rolvien ◽  
Fabiola Lange ◽  
Felix Nikolai Schmidt ◽  
...  
Keyword(s):  
Mouse Model ◽  
Osteogenesis Imperfecta ◽  
Bone Matrix ◽  
Bone Fragility ◽  
Osteogenesis Imperfecta Type ◽  
Matrix Quality ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Term Administration ◽  
And Function

AbstractThe recent identification of homozygous WNT1 mutations in individuals with osteogenesis imperfecta type XV (OI-XV) has suggested that WNT1 is a key ligand promoting the differentiation and function of bone-forming osteoblasts. Although such an influence was supported by subsequent studies, a mouse model of OI-XV remained to be established. Therefore, we introduced a previously identified disease-causing mutation (G177C) into the murine Wnt1 gene. Homozygous Wnt1G177C/G177C mice were viable and did not display defects in brain development, but the majority of 24-week-old Wnt1G177C/G177C mice had skeletal fractures. This increased bone fragility was not fully explained by reduced bone mass but also by impaired bone matrix quality. Importantly, the homozygous presence of the G177C mutation did not interfere with the osteoanabolic influence of either parathyroid hormone injection or activating mutation of LRP5, the latter mimicking the effect of sclerostin neutralization. Finally, transcriptomic analyses revealed that short-term administration of WNT1 to osteogenic cells induced not only the expression of canonical WNT signaling targets but also the expression of genes encoding extracellular matrix modifiers. Taken together, our data demonstrate that regulating bone matrix quality is a primary function of WNT1. They further suggest that individuals with WNT1 mutations should profit from existing osteoanabolic therapies.

scholarly journals Cyclic di-GMP Is Integrated Into a Hierarchal Quorum Sensing Network Regulating Antimicrobial Production and Biofilm Formation in Roseobacter Clade Member Rhodobacterales Strain Y4I

2021 ◽  
Vol 8 ◽  
Author(s):  
April C. Armes ◽  
Alison Buchan
Keyword(s):  
Quorum Sensing ◽  
Biofilm Formation ◽  
Homoserine Lactone ◽  
Roseobacter Clade ◽  
Partial Restoration ◽  
Microbial Biofilms ◽  
Expression Of Genes ◽  
Genes Encoding ◽  
Biofilm Development ◽  
And Function

Microbial biofilms associated with marine particulate organic matter carry out transformations that influence local and regional biogeochemical cycles. Early microbial colonizers are often hypothesized to “set the stage” for biofilm structure, dynamics, and function via N-acyl homoserine lactone (AHL)-mediated quorum sensing (QS). Production of AHLs, as well as antimicrobials, contributes to the colonization success of members of the Roseobacter clade. One member of this group of abundant marine bacteria, Rhodobacterales sp. Y4I, possesses two QS systems, phaRI (QS1) and pgaRI (QS2). Here, we characterize mutants in both QS systems to provide genetic evidence that the two systems work in hierarchical fashion to coordinate production of the antimicrobial indigoidine as well as biofilm formation. A mutation in pgaR (QS2) results in decreased expression of genes encoding both QS systems as well as those governing the biosynthesis of indigoidine. In contrast, mutations in QS1 did not significantly influence gene expression of QS2. Addition of exogenous AHLs to QS1 and QS2 mutants led to partial restoration of indigoidine production (45–60% of WT) for QS1 but not QS2. Mutational disruptions of QS1 had a more pronounced effect on biofilm development than those in QS2. Finally, we demonstrate that c-di-GMP levels are altered in QS and indigoidine biosynthesis Y4I mutants. Together, these results indicate that pgaRI (QS2) is at the top of a regulatory hierarchy governing indigoidine biosynthesis and that the global regulatory metabolite, c-di-GMP, is likely integrated into the QS circuitry of this strain. These findings provide mechanistic understanding of physiological processes that are important in elucidating factors driving competitiveness of Roseobacters in nature.

scholarly journals GPR84 signaling promotes intestinal mucosal inflammation via enhancing NLRP3 inflammasome activation in macrophages

2021 ◽  
Author(s):  
Qing Zhang ◽  
Lin-hai Chen ◽  
Hui Yang ◽  
You-chen Fang ◽  
Si-wei Wang ◽  
...  
Keyword(s):  
Nlrp3 Inflammasome ◽  
Intestinal Inflammation ◽  
Innate Immune ◽  
Mucosal Inflammation ◽  
Inflammasome Activation ◽  
Nlrp3 Inflammasome Activation ◽  
Inflammatory Stimuli ◽  
Monocytes And Macrophages ◽  
And Function ◽  
Inflammatory Macrophages

AbstractThe putative medium-chain free fatty acid receptor GPR84 is a G protein-coupled receptor primarily expressed in myeloid cells that constitute the innate immune system, including neutrophils, monocytes, and macrophages in the periphery and microglia in the brain. The fact that GPR84 expression in leukocytes is remarkably increased under acute inflammatory stimuli such as lipopolysaccharide (LPS) and TNFα suggests that it may play a role in the development of inflammatory and fibrotic diseases. Here we demonstrate that GPR84 is highly upregulated in inflamed colon tissues of active ulcerative colitis (UC) patients and dextran sulfate sodium (DSS)-induced colitis mice. Infiltrating GPR84+ macrophages are significantly increased in the colonic mucosa of both the UC patients and the mice with colitis. Consistently, GPR84−/− mice are resistant to the development of colitis induced by DSS. GPR84 activation imposes pro-inflammatory properties in colonic macrophages through enhancing NLRP3 inflammasome activation, while the loss of GPR84 prevents the M1 polarization and properties of proinflammatory macrophages. CLH536, a novel GPR84 antagonist discovered by us, suppresses colitis by reducing the polarization and function of pro-inflammatory macrophages. These results define a unique role of GPR84 in innate immune cells and intestinal inflammation, and suggest that GPR84 may serve as a potential drug target for the treatment of UC.

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