scholarly journals Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart

Development ◽  
2021 ◽  
Vol 148 (3) ◽  
pp. dev194563 ◽  
Author(s):  
Thomas J. Cahill ◽  
Xin Sun ◽  
Christophe Ravaud ◽  
Cristina Villa del Campo ◽  
Konstantinos Klaourakis ◽  
...  
Keyword(s):  
Heart Development ◽  
Lymphatic Endothelial Cell ◽  
Innate Immune ◽  
Lymphatic Endothelium ◽  
Developing Heart ◽  
Foetal Liver ◽  
Vessel Growth ◽  
And Function ◽  
Insight Into

ABSTRACTMacrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.

scholarly journals Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart

2020 ◽  
Author(s):  
Thomas J. Cahill ◽  
Xin Sun ◽  
Christophe Ravaud ◽  
Cristina Villa del Campo ◽  
Konstantinos Klaourakis ◽  
...  
Keyword(s):  
Heart Development ◽  
Lymphatic Vessel ◽  
Fetal Liver ◽  
Lymphatic Endothelial Cell ◽  
Vascular Plexus ◽  
Developing Heart ◽  
Vessel Growth ◽  
Summary Statement ◽  
And Function

AbstractMacrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that resident macrophages in the subepicardial compartment of the developing heart coincide with the emergence of new lymphatics and interact closely with the nascent lymphatic capillaries. Consequently, global macrophage-deficiency led to extensive vessel disruption with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and fetal liver. Moreover, Csf1r+ and Cx3cr1+ myeloid sub-lineages were found to play essential functions in the remodeling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was found to be required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature.Summary statementTissue-resident macrophages are indispensable mediators of lymphatic vessel formation during heart development and function to remodel the vascular plexus.

Regulation of hair follicle development by the TNF signal ectodysplasin and its receptor Edar

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2541-2553 ◽  
Author(s):  
Johanna Laurikkala ◽  
Johanna Pispa ◽  
Han-Sung Jung ◽  
Pekka Nieminen ◽  
Marja Mikkola ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Hair Follicles ◽  
Wild Type ◽  
Mutant Mouse Embryos ◽  
Anhidrotic Ectodermal Dysplasia ◽  
Embryonic Morphogenesis ◽  
Hair Follicle Development ◽  
And Function ◽  
Insight Into

X-linked and autosomal forms of anhidrotic ectodermal dysplasia syndromes (HED) are characterized by deficient development of several ectodermal organs, including hair, teeth and exocrine glands. The recent cloning of the genes that underlie these syndromes, ectodysplasin (ED1) and the ectodysplasin A receptor (EDAR), and their identification as a novel TNF ligand-receptor pair suggested a role for TNF signaling in embryonic morphogenesis. In the mouse, the genes of the spontaneous mutations Tabby (Ta) and downless (dl) were identified as homologs of ED1 and EDAR, respectively. To gain insight into the function of this signaling pathway in development of skin and hair follicles, we analyzed the expression and regulation of Eda and Edar in wild type as well as Tabby and Lef1 mutant mouse embryos. We show that Eda and Edar expression is confined to the ectoderm and occurs in a pattern that suggests a role of ectodysplasin/Edar signaling in the interactions between the ectodermal compartments and the formation and function of hair placodes. By using skin explant cultures, we further show that this signaling pathway is intimately associated with interactions between the epithelial and mesenchymal tissues. We also find that Ta mutants lack completely the placodes of the first developing tylotrich hairs, and that they do not show patterned expression of placodal genes, including Bmp4, Lef1, Shh, Ptch and Edar, and the genes for β-catenin and activin A. Finally, we identified activin as a mesenchymal signal that stimulates Edar expression and WNT as a signal that induces Eda expression, suggesting a hierarchy of distinct signaling pathways in the development of skin and hair follicles. In conclusion, we suggest that Eda and Edar are associated with the onset of ectodermal patterning and that ectodysplasin/edar signaling also regulates the morphogenesis of hair follicles.

scholarly journals TLR7 modulating B-cell immune responses in the spleen of C57BL/6 mice infected with Schistosoma japonicum

2021 ◽  
Vol 15 (11) ◽  
pp. e0009943
Author(s):  
Haixia Wei ◽  
Hongyan Xie ◽  
Jiale Qu ◽  
Anqi Xie ◽  
Shihao Xie ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Gene Knockout ◽  
Innate Immune ◽  
Wild Type ◽  
Cell Responses ◽  
Splenic Cells ◽  
And Function ◽  
Egg Antigen

B cells played an important role in Schistosoma infection-induced diseases. TLR7 is an intracellular member of the innate immune receptor. The role of TLR7 on B cells mediated immune response is still unclear. Here, C57BL/6 mice were percutaneously infected by S. japonicum for 5–6 weeks. The percentages and numbers of B cells increased in the infected mice (p < 0.05), and many activation and function associated molecules were also changed on B cells. More splenic cells of the infected mice expressed TLR7, and B cells were served as the main cell population. Moreover, a lower level of soluble egg antigen (SEA) specific antibody and less activation associated molecules were found on the surface of splenic B cells from S. japonicum infected TLR7 gene knockout (TLR7 KO) mice compared to infected wild type (WT) mice (p < 0.05). Additionally, SEA showed a little higher ability in inducing the activation of B cells from naive WT mice than TLR7 KO mice (p < 0.05). Finally, the effects of TLR7 on B cells are dependent on the activation of NF-κB p65. Altogether, TLR7 was found modulating the splenic B cell responses in S. japonicum infected C57BL/6 mice.

scholarly journals Role of Biological Sex in the Cardiovascular-Gut Microbiome Axis

2022 ◽  
Vol 8 ◽  
Author(s):  
Shuangyue Li ◽  
Georgios Kararigas
Keyword(s):  
Gut Microbiota ◽  
Gut Microbiome ◽  
Microbial Composition ◽  
Biological Sex ◽  
Technological Advances ◽  
Host Health ◽  
Health And Disease ◽  
And Function ◽  
Insight Into

There has been a recent, unprecedented interest in the role of gut microbiota in host health and disease. Technological advances have dramatically expanded our knowledge of the gut microbiome. Increasing evidence has indicated a strong link between gut microbiota and the development of cardiovascular diseases (CVD). In the present article, we discuss the contribution of gut microbiota in the development and progression of CVD. We further discuss how the gut microbiome may differ between the sexes and how it may be influenced by sex hormones. We put forward that regulation of microbial composition and function by sex might lead to sex-biased disease susceptibility, thereby offering a mechanistic insight into sex differences in CVD. A better understanding of this could identify novel targets, ultimately contributing to the development of innovative preventive, diagnostic and therapeutic strategies for men and women.

Mitochondrial Quality Control and Restraining Innate Immunity

2020 ◽  
Vol 36 (1) ◽  
pp. 265-289
Author(s):  
Andrew T. Moehlman ◽  
Richard J. Youle
Keyword(s):  
Innate Immunity ◽  
Quality Control ◽  
Neurodegenerative Diseases ◽  
Innate Immune ◽  
Interferon Response ◽  
Mitochondrial Quality Control ◽  
Selective Autophagy ◽  
Eukaryotic Organisms ◽  
And Function

Maintaining mitochondrial health is essential for the survival and function of eukaryotic organisms. Misfunctioning mitochondria activate stress-responsive pathways to restore mitochondrial network homeostasis, remove damaged or toxic proteins, and eliminate damaged organelles via selective autophagy of mitochondria, a process termed mitophagy. Failure of these quality control pathways is implicated in the pathogenesis of Parkinson's disease and other neurodegenerative diseases. Impairment of mitochondrial quality control has been demonstrated to activate innate immune pathways, including inflammasome-mediated signaling and the antiviral cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING)–regulated interferon response. Immune system malfunction is a common hallmark in many neurodegenerative diseases; however, whether inflammation suppresses or exacerbates disease pathology is still unclear. The goal of this review is to provide a historical overview of the field, describe mechanisms of mitochondrial quality control, and highlight recent advances on the emerging role of mitochondria in innate immunity and inflammation.

Emergence of the Unmarked in Indian Englishes with Different Substrates

2014 ◽  
Author(s):  
Caroline R. Wiltshire
Keyword(s):  
Second Language ◽  
Second Language Acquisition ◽  
Optimality Theory ◽  
Learning Algorithm ◽  
Indian English ◽  
Form And Function ◽  
First Languages ◽  
And Function ◽  
Insight Into

This study uses data from Indian English as a second language, spoken by speakers of five first languages, to illustrate and evaluate the role of the emergence of the unmarked (TETU) in phonological theory. The analysis focusses on word-final consonant devoicing and cluster reduction, for which the five Indian first languages have various constraints, while Indian English is relatively unrestricted. Variation in L2 Indian Englishes results from both transfer of L1 phonotactics and the emergence of the unmarked, accounted for within Optimality Theory. The use of a learning algorithm also allows us to test the relative importance of markedness and frequency and to evaluate the relative markedness of various clusters. Thus, data from Indian Englishes provides insight into the form and function of markedness constraints, as well as the mechanisms of Second Language Acquisition (SLA).

scholarly journals Structural Insight into the Mechanism of N-Linked Glycosylation by Oligosaccharyltransferase

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 624 ◽  
Author(s):  
Smita Mohanty ◽  
Bharat P Chaudhary ◽  
David Zoetewey
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Modification ◽  
Cell Communication ◽  
Reticulum Cell ◽  
Enzyme Complex ◽  
Single Polypeptide Chain ◽  
Domains Of Life ◽  
And Function ◽  
Insight Into

Asparagine-linked glycosylation, also known as N-linked glycosylation is an essential and highly conserved post-translational protein modification that occurs in all three domains of life. This modification is essential for specific molecular recognition, protein folding, sorting in the endoplasmic reticulum, cell–cell communication, and stability. Defects in N-linked glycosylation results in a class of inherited diseases known as congenital disorders of glycosylation (CDG). N-linked glycosylation occurs in the endoplasmic reticulum (ER) lumen by a membrane associated enzyme complex called the oligosaccharyltransferase (OST). In the central step of this reaction, an oligosaccharide group is transferred from a lipid-linked dolichol pyrophosphate donor to the acceptor substrate, the side chain of a specific asparagine residue of a newly synthesized protein. The prokaryotic OST enzyme consists of a single polypeptide chain, also known as single subunit OST or ssOST. In contrast, the eukaryotic OST is a complex of multiple non-identical subunits. In this review, we will discuss the biochemical and structural characterization of the prokaryotic, yeast, and mammalian OST enzymes. This review explains the most recent high-resolution structures of OST determined thus far and the mechanistic implication of N-linked glycosylation throughout all domains of life. It has been shown that the ssOST enzyme, AglB protein of the archaeon Archaeoglobus fulgidus, and the PglB protein of the bacterium Campylobactor lari are structurally and functionally similar to the catalytic Stt3 subunit of the eukaryotic OST enzyme complex. Yeast OST enzyme complex contains a single Stt3 subunit, whereas the human OST complex is formed with either STT3A or STT3B, two paralogues of Stt3. Both human OST complexes, OST-A (with STT3A) and OST-B (containing STT3B), are involved in the N-linked glycosylation of proteins in the ER. The cryo-EM structures of both human OST-A and OST-B complexes were reported recently. An acceptor peptide and a donor substrate (dolichylphosphate) were observed to be bound to the OST-B complex whereas only dolichylphosphate was bound to the OST-A complex suggesting disparate affinities of two OST complexes for the acceptor substrates. However, we still lack an understanding of the independent role of each eukaryotic OST subunit in N-linked glycosylation or in the stabilization of the enzyme complex. Discerning the role of each subunit through structure and function studies will potentially reveal the mechanistic details of N-linked glycosylation in higher organisms. Thus, getting an insight into the requirement of multiple non-identical subunits in the N-linked glycosylation process in eukaryotes poses an important future goal.

Invariant NKT Cells Regulate Osteoclast Development and Function Under Homeostatic and during Conditions of Immune Activation

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 104-104
Author(s):  
Ming Hu ◽  
J.H. Duncan Basssett ◽  
Lynette Danks ◽  
Emmanouil Spanoudakis ◽  
Ke Xu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Nkt Cells ◽  
Innate Immune ◽  
Small Subset ◽  
Developmental Defect ◽  
Invariant Nkt Cells ◽  
And Function ◽  
Actin Rings

Abstract Invariant NKT cells, a small subset of immunoregulatory T cells restricted by the glycolipid-presenting non-polymorphic CD1d molecule, are able to modulate a variety of innate and adaptive immune responses. Osteoclasts (OC) are bone resorbing polykaryons of hematopoietic lineage, that have the capacity to regulate myeloid cell egress from bone marrow (BM) thus making them an integral part of the innate immune response. We and others previously showed that NKT cells regulate hematopoiesis in mice as well as humans. In this work, we investigate the role of NKT cells in OC development and function in homeostasis and after their specific activation by the model glycolipid alpha-galactosylceramide (aGC). Using quantitative back scattered electron scanning microscopy, we found that TCR Ja18 −/− mice which selectively lack development of NKT cells, exhibit a moderate osteopetrotic phenotype affecting trabecular as well as cortical bone. Histologically, these mice had the same number of TRAP+ OC as WT mice suggesting a maturation rather developmental defect in the TCR Ja18 −/−-derived OC. In vitro differentiation in the presence of RANKL and M-CSF showed that while TCR Ja18 −/− BM cells are capable of forming multinucleated OC, these, as assessed by confocal microscopy, fail to form F-actin rings and sealing zone and thus are unable to resorb bone. Further underscoring the effect of NKT cells in this process, CD45.1+ BM cells highly purified from CD45.2+ WT/CD45.1+ TCRJa18 −/− mixed BM chimeras displayed restoration of their OC F-actin rings. Next we investigated whether in vivo activated NKT cells regulate OC function. We found that a single injection of aGC dramatically increased the number of CD3-B220-CD11b-c-fmshighc- kithigh BM OC progenitors and accelerated the in vitro development of OC in WT but not TCR Ja18 −/− mice. Furthermore, this resulted in high serum levels of IFN-g and IL-4 but not IL-1 or IL-17. An aGC-mediated increase of OC progenitors was observed in IFN-g −/− but not IL-4 −/−mice suggesting that NKT cell-derived IL-4 is the main cytokine promoting osteoclastogenesis in this context. Taken together, our data demonstrate a novel role of NKT cells in homeostatic bone mass regulation and in the orchestration of innate immune responses through regulation of OC development and function.

scholarly journals Role of Specialized Pro-Resolving Mediators in Modifying Host Defense and Decreasing Bacterial Virulence

Molecules ◽  
2021 ◽  
Vol 26 (22) ◽  
pp. 6970
Author(s):  
Julianne M. Thornton ◽  
Kingsley Yin
Keyword(s):  
Host Defense ◽  
Host Response ◽  
Tissue Repair ◽  
Defense Mechanisms ◽  
Neutrophil Migration ◽  
Bacterial Virulence ◽  
Innate Immune ◽  
Bioactive Fatty Acids ◽  
Insight Into

Bacterial infection activates the innate immune system as part of the host’s defense against invading pathogens. Host response to bacterial pathogens includes leukocyte activation, inflammatory mediator release, phagocytosis, and killing of bacteria. An appropriate host response requires resolution. The resolution phase involves attenuation of neutrophil migration, neutrophil apoptosis, macrophage recruitment, increased phagocytosis, efferocytosis of apoptotic neutrophils, and tissue repair. Specialized Pro-resolving Mediators (SPMs) are bioactive fatty acids that were shown to be highly effective in promoting resolution of infectious inflammation and survival in several models of infection. In this review, we provide insight into the role of SPMs in active host defense mechanisms for bacterial clearance including a new mechanism of action in which an SPM acts directly to reduce bacterial virulence.

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