The Lymphotoxin β Receptor Is Essential for Upregulation of IFN-Induced Guanylate-Binding Proteins and Survival after Toxoplasma gondii Infection

Lymphotoxin β receptor (LTβR) signaling plays an important role in efficient initiation of host responses to a variety of pathogens, encompassing viruses, bacteria, and protozoans via induction of the type I interferon response. The present study reveals that after Toxoplasma gondii infection, LTβR−/− mice show a substantially reduced survival rate when compared to wild-type mice. LTβR−/− mice exhibit an increased parasite load and a more pronounced organ pathology. Also, a delayed increase of serum IL-12p40 and a failure of the protective IFNγ response in LTβR−/− mice were observed. Serum NO levels in LTβR−/− animals rose later and were markedly decreased compared to wild-type animals. At the transcriptional level, LTβR−/− animals exhibited a deregulated expression profile of several cytokines known to play a role in activation of innate immunity in T. gondii infection. Importantly, expression of the IFNγ-regulated murine guanylate-binding protein (mGBP) genes was virtually absent in the lungs of LTβR−/− mice. This demonstrates clearly that the LTβR is essential for the induction of a type II IFN-mediated immune response against T. gondii. The pronounced inability to effectively upregulate host defense effector molecules such as GBPs explains the high mortality rates of LTβR−/− animals after T. gondii infection

Wound repair and scarring of genital skin

Aim: Scarring is a physiological process in adult wound repair. Although keratinocytes and fibroblasts are the main cell types of the skin, they differ in migration behaviour and inflammatory responses depending on their location in the body. The aim of this article is to describe wound repair in genital skin and to depict differences with regard to skin anatomy and cellular responses to inflammatory stimuli in acute and chronic wound healing.Methods: This report reviews data from patients undergoing reconstructive and aesthetic plastic surgery as well as published studies on genital wound repair. Genital surgery comprised plastic reconstructive surgery after urological interventions of biological men and women, tissue from trans-males and trans-females undergoing gender reassignment surgery and tissue from patients undergoing aesthetic genital surgery. The cohort comprised a total of 68 patients (32.9 ± 11.3 years), of which 31 were male (mean 30.4 ± 9.3 years) and 37 were female (34.9 ± 12.5 years; mean ± SD).Results: Wound healing in genital skin markedly differs from other areas of the body due to its anatomical features, microbiome, and elevated hormonal responsiveness. Human genital skin is highly extensible and unusually rich in elastic fibres, and it lacks the mechanical anchorage and tensile properties typical of non-genital regions. Acute injury resolves rapidly due, in part, to rapid resolution of the inflammatory response. In contrast to scarring responses on other body surfaces, genital skin wounding is resolved by shrinkage or fistula formation.Conclusion: The embryological origins of genital skin fibroblasts, together with the gender-specific hormonal environment, contribute to the unique phenotype and healing properties of genital skin. When performing genital surgery, it is of utmost importance to be aware of the differing responsiveness of genital tissue to trauma, surgery, and repair

Origin and differentiation trajectories of fibroblastic reticular cells in the splenic white pulp

The splenic white pulp is underpinned by poorly characterized stromal cells that demarcate distinct immune cell microenvironments. Here we establish fibroblastic reticular cell (FRC)-specific fate-mapping in mice to define their embryonic origin and differentiation trajectories. Our data show that all reticular cell subsets descend from multipotent progenitors emerging at embryonic day 19.5 from periarterial progenitors. Commitment of FRC progenitors is concluded during the first week of postnatal life through occupation of niches along developing central arterioles. Single cell transcriptomic analysis facilitated deconvolution of FRC differentiation trajectories and indicated that perivascular reticular cells function both as adult lymphoid organizer cells and mural cell progenitors. The lymphotoxin-β receptor-independent sustenance of postnatal progenitor stemness unveils that systemic immune surveillance in the splenic white pulp is governed through subset specification of reticular cells from a multipotent periarterial progenitor cell. In sum, the finding that discrete signaling events in perivascular niches determine the differentiation trajectories of reticular cell networks explains the development of distinct microenvironmental niches in secondary and tertiary lymphoid tissues that are crucial for the induction and regulation of innate and adaptive immune processes

Stringent regulation of DNA repair during human hematopoietic differentiation: a gene expression and functional analysis.

Contains fulltext : 49693.pdf (publisher's version ) (Closed access)For the lymphohematopoietic system, maturation-dependent alterations in DNA repair function have been demonstrated. Because little information is available on the regulatory mechanisms underlying these changes, we have correlated the expression of DNA damage response genes and the functional repair capacity of cells at distinct stages of human hematopoietic differentiation. Comparing fractions of mature (CD34-), progenitor (CD34+ 38+), and stem cells (CD34+ 38-) isolated from umbilical cord blood, we observed: 1) stringently regulated differentiation-dependent shifts in both the cellular processing of DNA lesions and the expression profiles of related genes and 2) considerable interindividual variability of DNA repair at transcriptional and functional levels. The respective repair phenotype was found to be constitutively regulated and not dominated by adaptive response to acute DNA damage. During blood cell development, the removal of DNA adducts, the resealing of repair gaps, the resistance to DNA-reactive drugs clearly increased in stem or mature compared with progenitor cells of the same individual. On the other hand, the vast majority of differentially expressed repair genes was consistently upregulated in the progenitor fraction. A positive correlation of repair function and transcript levels was found for a small number of genes such as RAD23 or ATM, which may serve as key regulators for DNA damage processing via specific pathways. These data indicate that the organism might aim to protect the small number of valuable slow dividing stem cells by extensive DNA repair, whereas fast-proliferating progenitor cells, once damaged, are rather eliminated by apoptosis