Single-cell RNA-seq reveals ectopic and aberrant lung-resident cell populations in idiopathic pulmonary fibrosis.

We provide a single-cell atlas of idiopathic pulmonary fibrosis (IPF), a fatal interstitial lung disease, by profiling 312,928 cells from 32 IPF, 28 smoker and nonsmoker controls, and 18 chronic obstructive pulmonary disease (COPD) lungs. Among epithelial cells enriched in IPF, we identify a previously unidentified population of aberrant basaloid cells that coexpress basal epithelial, mesenchymal, senescence, and developmental markers and are located at the edge of myofibroblast foci in the IPF lung. Among vascular endothelial cells, we identify an ectopically expanded cell population transcriptomically identical to bronchial restricted vascular endothelial cells in IPF.

Predator-induced phenotypic plasticity of shape and behavior: parallel and unique patterns across sexes and species.

Phenotypic plasticity is often an adaptation of organisms to cope with temporally or spatially heterogenous landscapes. Like other adaptations, one would predict that different species, populations, or sexes might thus show some degree of parallel evolution of plasticity, in the form of parallel reaction norms, when exposed to analogous environmental gradients. Indeed, one might even expect parallelism of plasticity to repeatedly evolve in multiple traits responding to the same gradient, resulting in integrated parallelism of plasticity.

Interleukin-36 potently stimulates human M2 macrophages, Langerhans cells and keratinocytes to produce pro-inflammatory cytokines.

Interleukin (IL)-36 cytokines belong to the IL-1 family and include three agonists, IL-36 α, β and γ and one inhibitor, IL-36 receptor antagonist (IL-36Ra). IL-36 and IL-1 (α and β) activate similar intracellular pathways via their related heterodimeric receptors, IL-36R/IL-1RAcP and IL-1R1/IL-1RAcP, respectively. However, excessive IL-36 versus IL-1 signaling induces different phenotypes in humans, which may be related to differential expression of their respective receptors.

Sex ratio variation shapes the ecological effects of a globally introduced freshwater fish.

Sex ratio and sexual dimorphism have long been of interest in population and evolutionary ecology, but consequences for communities and ecosystems remain untested. Sex ratio could influence ecological conditions whenever sexual dimorphism is associated with ecological dimorphism in species with strong ecological interactions. We tested for ecological implications of sex ratio variation in the sexually dimorphic western mosquitofish, Gambusia affinis.

Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy.

Despite the availability of several therapies for rheumatoid arthritis (RA) that target the immune system, a large number of RA patients fail to achieve remission. Joint-lining cells, called fibroblast-like synoviocytes (FLS), become activated during RA and mediate joint inflammation and destruction of cartilage and bone. We identify RPTPσ, a transmembrane tyrosine phosphatase, as a therapeutic target for FLS-directed therapy.

Immune modulation by butyrophilins.

The B7 family of co-stimulatory molecules has an important role in driving the activation and inhibition of immune cells. Evolving data have shown that a related family of molecules - the butyrophilins - have similar immunomodulatory functions to B7 family members and may represent a novel subset of co-stimulatory molecules. These studies have taken the field by surprise, as the butyrophilins were previously thought to only be important in lactation and milk production.

Protein tyrosine phosphatase expression profile of rheumatoid arthritis fibroblast-like synoviocytes: a novel role of SH2 domain-containing phosphatase 2 as a modulator of invasion and survival.

Objective: The fibroblast-like synoviocytes (FLS) in the synovial intimal lining of the joint are key mediators of inflammation and joint destruction in rheumatoid arthritis (RA). In RA, these cells aggressively invade the extracellular matrix, producing cartilage-degrading proteases and inflammatory cytokines. The behavior of FLS is controlled by multiple interconnected signal transduction pathways involving reversible phosphorylation of proteins on tyrosine residues.

Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core.

The optimization of a series of S1P1 agonists with limited activity against S1P3 is reported. A polar headgroup was used to improve the physicochemical and pharmacokinetic parameters of lead quinolinone 6. When dosed orally at 1 and 3 mg/kg, the azahydroxymethyl analogue 22 achieved statistically significant lowering of circulating blood lymphocytes 24 h postdose.

Quinolinone-based agonists of S1P₁: use of a N-scan SAR strategy to optimize in vitro and in vivo activity.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.

4-Methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide: A Potent and Selective Agonist of S1P1.

The sphingosine-1-phosphate-1 receptor (S1P1) and its endogenous ligand sphingosine-1-phosphate (S1P) cooperatively regulate lymphocyte trafficking from the lymphatic system. Herein, we disclose 4-methoxy-N-[2-(trifluoromethyl)biphenyl-4-ylcarbamoyl]nicotinamide (8), an uncommon example of a synthetic S1P1 agonist lacking a polar headgroup, which is shown to effect dramatic reduction of circulating lymphocytes (POC = -78%) in rat 24 h after a single oral dose (1 mg/kg). The excellent potency that 8 exhibits toward S1P1 (EC50 = 0.

Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis.

Background: Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival.

Diverse functions of reactive cysteines facilitate unique biosynthetic processes of aggregate-prone interleukin-31.

Interleukin-31 (IL-31) is a member of the four helical-bundle gp130/IL-6 cytokine family. Despite its implicated roles in inflammatory diseases, the biosynthetic processes of IL-31 have been poorly investigated. A detailed understanding of IL-31 biosynthesis and the nature of ligand-receptor interactions can provide insights into effective strategies for the design of therapeutic approaches.

Melting Alpine glaciers enrich high-elevation lakes with reactive nitrogen.

Alpine glaciers have receded substantially over the last century in many regions of the world. Resulting changes in glacial runoff not only affect the hydrological cycle, but can also alter the physical (i.e.

Gatekeepers of intestinal inflammation.

The intestine is subjected to a barrage of insults from food, bacterial flora, and pathogens. Despite this constant antigenic challenge, the mucosal tissues lining the intestinal tract remain largely under control. The mechanisms regulating the homeostatic balance in the gut have been investigated for many years by many groups, but the precise nature of the regulatory control remains elusive.

Recent developments in IBD and the B7 family of costimulatory molecules.

The cells and tissues of the intestinal tract are subjected to a constant onslaught of antigenic challenge from both beneficial and harmful pathogens. Despite this constant stimulation, the host is able to maintain a relatively stable environment, often referred to as 'a controlled state of inflammation'. In patients with chronic inflammatory bowel disease, this controlled state of inflammation is lost.

Regulation of costimulation in the era of butyrophilins.

The butyrophilin and butyrophilin-like superfamily of molecules has garnered attention in the immunology world in the past few years as a result of the observation that the butyrophilin-like 2 molecule, BTNL2, can alter T cell responsiveness. Additional interest in this superfamily solidified following the discovery that genetic polymorphisms in BTNL2 are associated with predisposition to many human diseases. In this review, we will provide an overview of the members comprising the butyrophilin superfamily of molecules.

Mechanisms of oncostatin M-induced pulmonary inflammation and fibrosis.

Oncostatin M (OSM), an IL-6 family cytokine, has been implicated in a number of biological processes including the induction of inflammation and the modulation of extracellular matrix. In this study, we demonstrate that OSM is up-regulated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis and scleroderma, and investigate the pathological consequences of excess OSM in the lungs. Delivery of OSM to the lungs of mice results in a significant recruitment of inflammatory cells, as well as a dose-dependent increase in collagen deposition in the lungs, with pathological correlates to characteristic human interstitial lung disease.

Combined analysis of monocyte and lymphocyte messenger RNA expression with serum protein profiles in patients with scleroderma.

Objective: We attempted to elucidate possible pathogenetic mechanisms in scleroderma by analysis of gene expression patterns of purified monocytes and lymphocytes, as well as protein profiles of cytokines and growth factors.

Methods: Expression analysis was performed on messenger RNA (mRNA) from cells that had been purified with magnetic beads. Plasma samples from the same patients were used for multiplex cytokine analysis.

Considerations for the sensible use of rodent models of inflammatory disease in predicting efficacy of new biological therapeutics in the clinic.

Successful therapeutics for treating autoimmune and inflammatory diseases must be able to significantly dampen, and ideally reverse, the complex processes involved in the manifestation of inflammatory pathology in intact tissues and organs. Studies on human cells and tissues - both normal and diseased - are obviously critical for moving forward with a particular therapeutic strategy, but these types of studies are oftentimes limited in their complexity and usually fail to fully replicate the biology of the intact inflammatory environment and disease process. It is for this reason that development of a new drug generally relies on data generated from in vivo animal models that have been created to mimic aspects of the complex disease process in whole organs and whole animals.

Lymphotoxin beta receptor (Lt betaR): dual roles in demyelination and remyelination and successful therapeutic intervention using Lt betaR-Ig protein.

Inflammation mediated by macrophages is increasingly found to play a central role in diseases and disorders that affect a myriad of organs, prominent among these are diseases of the CNS. The neurotoxicant-induced, cuprizone model of demyelination is ideally suited for the analysis of inflammatory events. Demyelination on exposure to cuprizone is accompanied by predictable microglial activation and astrogliosis, and, after cuprizone withdrawal, this activation reproducibly diminishes during remyelination.

Development of NG2 neural progenitor cells requires Olig gene function.

In the adult central nervous system, two distinct populations of glial cells expressing the chondroitin sulfate proteoglycan NG2 have been described: bipolar progenitor cells and more differentiated "synantocytes." These cells have diverse neurological functions, including critical roles in synaptic transmission, repair, and regeneration. Despite their potential importance, the genetic factors that regulate NG2 cell development are poorly understood, and the relationship of synantocytes to the oligodendroglial lineage, in particular, remains controversial.