Lung injury-induced activated endothelial cell states persist in aging-associated progressive fibrosis.

Progressive lung fibrosis is associated with poorly understood aging-related endothelial cell dysfunction. To gain insight into endothelial cell alterations in lung fibrosis we performed single cell RNA-sequencing of bleomycin-injured lungs from young and aged mice. Analysis reveals activated cell states enriched for hypoxia, glycolysis and YAP/TAZ activity in ACKR1+ venous and TrkB+ capillary endothelial cells.

Conditions that promote transcellular neutrophil migration in vivo.

Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have previously shown that genetically replacing VE-cadherin with a VE-cadherin-α-catenin (VEC-αC) fusion construct-which binds constitutively to actin-obstructs junctions, and blocks leukocyte extravasation in lung, skin and postcapillary venules of cremaster muscle. However, neutrophil recruitment into the inflamed peritoneal cavity was unimpaired.

Slow integrin-dependent migration organizes networks of tissue-resident mast cells.

Immune cell locomotion is associated with amoeboid migration, a flexible mode of movement, which depends on rapid cycles of actin polymerization and actomyosin contraction. Many immune cells do not necessarily require integrins, the major family of adhesion receptors in mammals, to move productively through three-dimensional tissue spaces. Instead, they can use alternative strategies to transmit their actin-driven forces to the substrate, explaining their migratory adaptation to changing external environments.

Single Cell Transcriptomics of Fibrotic Lungs Unveils Aging-associated Alterations in Endothelial and Epithelial Cell Regeneration.

Lung regeneration deteriorates with aging leading to increased susceptibility to pathologic conditions, including fibrosis. Here, we investigated bleomycin-induced lung injury responses in young and aged mice at single-cell resolution to gain insights into the cellular and molecular contributions of aging to fibrosis. Analysis of 52,542 cells in young (8 weeks) and aged (72 weeks) mice identified 15 cellular clusters, many of which exhibited distinct injury responses that associated with age.

Specialized transendothelial dendritic cells mediate thymic T-cell selection against blood-borne macromolecules.

T cells undergo rigorous selection in the thymus to ensure self-tolerance and prevent autoimmunity, with this process requiring innocuous self-antigens (Ags) to be presented to thymocytes. Self-Ags are either expressed by thymic stroma cells or transported to the thymus from the periphery by migratory dendritic cells (DCs); meanwhile, small blood-borne peptides can access the thymic parenchyma by diffusing across the vascular lining. Here we describe an additional pathway of thymic Ag acquisition that enables circulating antigenic macromolecules to access both murine and human thymi.

ACKR1 favors transcellular over paracellular T-cell diapedesis across the blood-brain barrier in neuroinflammation in vitro.

The migration of CD4 effector/memory T cells across the blood-brain barrier (BBB) is a critical step in MS or its animal model, EAE. T-cell diapedesis across the BBB can occur paracellular, via the complex BBB tight junctions or transcellular via a pore through the brain endothelial cell body. Making use of primary mouse brain microvascular endothelial cells (pMBMECs) as in vitro model of the BBB, we here directly compared the transcriptome profile of pMBMECs favoring transcellular or paracellular T-cell diapedesis by RNA sequencing (RNA-seq).

Age-related changes in the local milieu of inflamed tissues cause aberrant neutrophil trafficking and subsequent remote organ damage.

Aging is associated with dysregulated immune functions. Here, we investigated the impact of age on neutrophil diapedesis. Using confocal intravital microscopy, we found that in aged mice, neutrophils adhered to vascular endothelium in inflamed tissues but exhibited a high frequency of reverse transendothelial migration (rTEM).

Introduction to the Immune System.

The immune system in a broad sense is a mechanism that allows a living organism to discriminate between "self" and "nonself." Examples of immune systems occur in multicellular organisms as simple and ancient as sea sponges. In fact, complex multicellular life would be impossible without the ability to exclude external life from the internal environment.

Distinct Compartmentalization of the Chemokines CXCL1 and CXCL2 and the Atypical Receptor ACKR1 Determine Discrete Stages of Neutrophil Diapedesis.

Neutrophils require directional cues to navigate through the complex structure of venular walls and into inflamed tissues. Here we applied confocal intravital microscopy to analyze neutrophil emigration in cytokine-stimulated mouse cremaster muscles. We identified differential and non-redundant roles for the chemokines CXCL1 and CXCL2, governed by their distinct cellular sources.

Spinal cord injury-induced immunodeficiency is mediated by a sympathetic-neuroendocrine adrenal reflex.

Acute spinal cord injury (SCI) causes systemic immunosuppression and life-threatening infections, thought to result from noradrenergic overactivation and excess glucocorticoid release via hypothalamus-pituitary-adrenal axis stimulation. Instead of consecutive hypothalamus-pituitary-adrenal axis activation, we report that acute SCI in mice induced suppression of serum norepinephrine and concomitant increase in cortisol, despite suppressed adrenocorticotropic hormone, indicating primary (adrenal) hypercortisolism. This neurogenic effect was more pronounced after high-thoracic level (Th1) SCI disconnecting adrenal gland innervation, compared with low-thoracic level (Th9) SCI.

Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis.

Healthy individuals of African ancestry have neutropenia that has been linked with the variant rs2814778(G) of the gene encoding atypical chemokine receptor 1 (ACKR1). This polymorphism selectively abolishes the expression of ACKR1 in erythroid cells, causing a Duffy-negative phenotype. Here we describe an unexpected fundamental role for ACKR1 in hematopoiesis and provide the mechanism that links its absence with neutropenia.

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues.

Background: Intravascular leukocyte recruitment in most vertebrate tissues is restricted to postcapillary and collecting venules, whereas capillaries and arterioles usually support little or no leukocyte adhesion. This segmental restriction is thought to be mediated by endothelial, rather than hemodynamic, differences. The underlying mechanisms are largely unknown, in part because effective tools to distinguish, isolate, and analyze venular endothelial cells (V-ECs) and non-venular endothelial cells (NV-ECs) have been unavailable.

In vivo endothelial siRNA delivery using polymeric nanoparticles with low molecular weight.

Dysfunctional endothelium contributes to more diseases than any other tissue in the body. Small interfering RNAs (siRNAs) can help in the study and treatment of endothelial cells in vivo by durably silencing multiple genes simultaneously, but efficient siRNA delivery has so far remained challenging. Here, we show that polymeric nanoparticles made of low-molecular-weight polyamines and lipids can deliver siRNA to endothelial cells with high efficiency, thereby facilitating the simultaneous silencing of multiple endothelial genes in vivo.

Nociceptive sensory neurons drive interleukin-23-mediated psoriasiform skin inflammation.

The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres.

Introduction to the immune system.

The immune system in a broad sense is a mechanism that allows a living organism to discriminate between "self" and "non-self." Examples of immune systems occur in multicellular organisms as simple and ancient as sea sponges. In fact, complex multicellular life would be impossible without the ability to exclude external life from the internal environment.

Of origins and pedigrees: lineage tracing of dendritic cells.

Understanding the ontogeny of distinct hematopoietic cell types remains a challenge. In this issue, Schraml et al. contribute to unraveling the complexity of a central component of the mononuclear phagocyte system by using a new in vivo approach to trace the progeny of common dendritic cell precursors.

Endothelial heparan sulfate controls chemokine presentation in recruitment of lymphocytes and dendritic cells to lymph nodes.

Heparan sulfate can bind several adhesion molecules involved in lymphocyte trafficking. However, the in vivo function of endothelial heparan sulfate in lymphocyte homing and stimulation of the immune response has not been elucidated. Here, we generated mutant mice deficient in the enzyme Ext1, which is required for heparan sulfate synthesis, in a Tek-dependent and inducible manner.

Peritoneal B-cell subsets in the genus Mus: their role in innate immunity.

In this review, we demonstrate that wild-derived mouse strains (wild-DMS) represent a useful tool for dissecting the immune system. We confirm and extend the notion that we and others have previously advanced, which is that common laboratory mice are not fully representative of the whole genus Mus. We illustrate how wild-DMS helped us to unveil a novel B-cell population that, in contrast to the B-1 cell population, is present in the entire genus Mus, including common laboratory mice.

Wild-derived mouse strains, a valuable model to study B cell responses.

In the present report, we revisited the B cell responsiveness of 7 wild-derived mouse strains to various toll-like receptor ligands (TLR-L). We found that 2 of them, namely PWK and STF presented profound defects in B cell proliferative responses to most of the TLR-L. Yet, their macrophage responses were largely unaffected, suggesting that regulation of TLR pathways are distinct in B cells and macrophages.

The Bw cells, a novel B cell population conserved in the whole genus Mus.

In common laboratory mouse strains, which are derived from the crossing between three subspecies, peritoneal B cells are enriched in B-1a cells characterized by the CD5(+)Mac-1(+)B220(low)IgM(high)IgD(low)CD43(+)CD9(+) phenotype. Intriguingly in other vertebrates, CD5(+)Mac-1(+) cells have never been found in a specific anatomic site. To ascertain the peculiarity of the CD5(+) peritoneal B cells in laboratory mice, we analyzed the peritoneal B cell subsets in 9 inbred and 39 outbred wild-derived mouse strains belonging to 13 different species/subspecies.

IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN.

IMGT, the international ImMunoGeneTics information system (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins of the immune system (RPI) of human and other vertebrates.