THY1 is a cell surface protein of mature neurons. Although the Thy1 promoter is widely used as a neuron-specific promoter for transgenic expression, the role of the endogenous THY1 protein in the brain remains largely unknown. As THY1 receptors are expressed on astrocytes, THY1 may mediate signaling between both cell types. We therefore investigated the role of THY1 signaling in neuron-astrocyte communication using a full as well as a neuron-specific Thy1-knockout mouse model. Compared to wild-type mice, aged individuals of both strains exhibited an increased expression of a subset of astrocyte activation-associated genes, such as glial fibrillary acidic protein (Gfap), vimentin (Vim), and tenascin C (Tnc), whereas others appeared unaffected. Importantly, a cortical injury caused a permanent astrocytic activation in mice with neuronal Thy1 deletion, reflected by persistent high GFAP expression. The THY1-associated modulation of gene expression was confirmed in primary astrocytes cultured with or without recombinant THY1. Moreover, functional assays indicate that THY1 inhibits astrocyte proliferation while promoting apoptosis. Interaction of neuronal THY1 with ITGB1 on astrocytes was identified to be responsible for the THY1-mediated control of astrocyte activation. These data strongly suggest that THY1-bearing neurons keep astrocytes in a quiescent state. Consequently, a depletion of THY1 supports the development of a partially activated astrocyte phenotype characterized by increased expression of intermediate filaments, increased proliferative capacity, and reduced cell death. Our findings demonstrate that neuronal THY1 is a still unrecognized novel regulator in the communication between astrocytes and neurons involved in the maintenance and restoration of tissue homeostasis in the brain.

Effective tissue response to infection and injury essentially relies on the fine-tuned induction and subsequent resolution of inflammation. Recent research highlighted multiple functions of dermal white adipose tissue (dWAT) beyond its traditional role as an energy reservoir. However, in contrast to other fat depots, there are only limited data about putative immune-regulatory functions of dWAT. Therefore, we investigated the impact of dWAT in the control of an acute skin inflammation. Skin inflammation triggers the activation of dWAT. In turn, soluble mediators of activated dWAT stimulate the expression of numerous genes controlling skin inflammation including the Th2 cell cytokines interleukin-4 (IL-4) and interleukin-13 (IL-13) in myeloid cells in vitro. Consistently, myeloid cells isolated from inflamed skin showed a significant upregulation of IL-4/13 expression compared to those isolated from healthy skin. Mechanistically, we demonstrate that interleukin-33 (IL-33) released from activated dWAT is responsible for IL-4/13 stimulation in myeloid cells. Interestingly, obesity attenuates IL-33 secretion in dWAT during inflammation resulting in decreased IL-4 and IL-13 expression in myeloid cells.Our data reveal an IL-33 – IL-4/13 signaling cascade initiated from dWAT in a Th2 independent context of inflammation that may contribute to limitation of inflammation. This cascade seems to be disturbed in obese individuals with prolonged inflammation.

ABSTRACT Background and Aim Portal myofibroblasts (PMF) are known to be critical in bile duct injury, but their role in liver fibrogenesis remains underexplored. Thy‐1, an adhesion molecule detected as soluble Thy‐1 (sThy‐1) in serum, is primarily expressed by portal myofibroblasts (PMF) and, to a lesser extent, hepatic stellate cells (HSC), serving as a marker for myofibroblast activity in liver pathology. This study aimed to elucidate the correlation between Thy‐1 expression in liver histology and sThy‐1 levels in serum with the degree of liver fibrosis in patients with primary biliary cholangitis (PBC) and metabolic dysfunction‐associated steatotic liver disease (MASLD). Methods Liver histology samples were stained for Thy‐1, and sThy‐1 was measured using an enzyme‐linked immunosorbent assay (ELISA). Results In patients with PBC and MASLD, an association between portal Thy‐1 expression and the extent of fibrosis was observed. Notably, while sinusoidal Thy‐1 expression aligned with fibrosis severity in PBC (p < 0.001), this association was not statistically significant in MASLD (p = 0.059). Moreover, variations in soluble Thy‐1 levels paralleled the progression from mild to advanced fibrosis stages in PBC. Conclusions Thy‐1 expression levels were associated with the severity of fibrosis, which could support its role in monitoring the presence and activity of myofibroblasts in liver diseases.

Background and AimsSteatotic liver disease (SLD) is generally considered to represent a hepatic manifestation of metabolic syndrome and includes a disease spectrum comprising isolated steatosis, metabolic dysfunction-associated steatohepatitis, liver fibrosis and ultimately cirrhosis. A better understanding of the detailed underlying pathogenic mechanisms of this transition is crucial for the design of new and efficient therapeutic interventions. Thymocyte differentiation antigen (Thy-1, also known as CD90) expression on fibroblasts controls central functions relevant to fibrogenesis, including proliferation, apoptosis, cytokine responsiveness, and myofibroblast differentiation.MethodsThe impact of Thy-1 on the development of SLD and progression to fibrosis was investigated in high-fat diet (HFD)-induced SLD wild-type and Thy-1-deficient mice. In addition, the serum soluble Thy-1 (sThy-1) concentration was analysed in patients with metabolic dysfunction-associated SLD stratified according to steatosis, inflammation, or liver fibrosis using noninvasive markers.ResultsWe demonstrated that Thy-1 attenuates the development of fatty liver and the expression of profibrogenic genes in the livers of HFD-induced SLD mice. Mechanistically, Thy-1 directly inhibits the profibrotic activation of nonparenchymal liver cells. In addition, Thy-1 prevents palmitic acid-mediated amplification of the inflammatory response of myeloid cells, which might indirectly contribute to the pronounced development of liver fibrosis in Thy-1-deficient mice. Serum analysis of patients with metabolically associated steatotic liver disease syndrome revealed that sThy-1 expression is correlated with liver fibrosis status, as assessed by liver stiffness, the Fib4 score, and the NAFLD fibrosis score.ConclusionOur data strongly suggest that Thy-1 may function as a fibrosis-protective factor in mouse and human SLD.

Bone consists of a complex mineralised matrix that is maintained by a controlled equilibrium of synthesis and resorption by different cell types. Hyaluronan (HA) is an important glycosaminoglycan in many tissues including bone.Previously, the importance of HA synthesis for bone development during embryogenesis has been shown. We therefore investigated whether HA synthesis is involved in adult bone turnover and whether abrogation of HA synthesis in adult mice would alter bone quality.To achieve complete abrogation of HA synthesis in adult mice, we generated a novel Has-total knockout (Has-tKO) mouse model in which a constitutive knockout of Has1 and Has3 was combined with an inducible, Ubc-Cre-driven Has2 knockout.By comparing bone tissue from wild-type, Has1,3 double knockout and Has-tKO mice, we demonstrate that Has2-derived HA mainly contributes to the HA content in bone. Furthermore, Has-tKO mice show a significant decrease of bone integrity in trabecular and cortical bone, as shown by µ-CT analysis. These effects are detectable as early as five weeks after induced Has2 deletion, irrespective of sex and progress with age.Mesenchymal stem cells (MSC) during osteogenic differentiation in vitro showed that Has2 expression is increased while Has3 expression is decreased during differentiation. Furthermore, the complete abrogation of HA synthesis results in significantly reduced osteogenic differentiation as indicated by reduced marker gene expression (Runx-2, Tnalp, Osterix) as well as alizarin red staining. RNAseq analysis revealed that MSC from Has-tKO are characterised by decreased expression of genes annotated for bone and organ development, whereas expression of genes associated with chemokine related interactions and cytokine signalling is increased.Taken together, we present a novel mouse model with complete deletion of HA synthases in adult mice which has the potential to study HA function in different organs and during age-related HA reduction. With respect to bone, HA synthesis is important for maintaining bone integrity, presumably based on the strong effect of HA on osteogenic differentiation.

Chronic non-healing wounds are characterized by persistent inflammation, excessive matrix-degrading proteolytic activity and compromised extracellular matrix (ECM) synthesis. Previous studies showed that S100A8/A9 are strongly dysregulated in delayed wound healing and impair the proper function of immune cells. Here, we demonstrate an unrecognized pathological function of S100A9 overexpression in wounds with impaired healing that directly affects ECM functions in fibroblasts. S100A9 was analyzed in two different mouse models mimicking the features of the two most prominent types of non-healing wounds in humans. Db/db mice were used as a model for diabetes-associated impaired wound healing. Iron-overloaded mice were used to mimic the conditions of impaired wound healing in chronic venous leg ulcers. The skin wounds of both mouse models are characterized by delayed wound closure, high and sustained expression of pro-inflammatory mediators and a substantially decreased ECM deposition, all together the hallmarks of non-healing wounds in humans. The wounds of both mouse models also present a solid and prolonged expression of S100A8 and S100A9 that coincides with a compromised ECM deposition and that was confirmed in chronic wounds in humans. Mechanistically, we reveal that S100A9 directly affects ECM deposition by shifting the balance of expression of ECM proteins and ECM degrading enzymes in fibroblasts via toll-like-receptor 4-dependent signaling. Consequently, blocking S100A9 during delayed wound healing in db/db mice restores fibroblast ECM functions eliciting increased matrix deposition. Our data indicate that the dysregulation of S100A9 directly contributes to a compromised ECM deposition in chronic wounds and further suggests S100A9 as a promising therapeutic target to improve tissue repair in chronic wounds.

RATIONALE:Psoriasis is a chronic inflammatory skin disease involving different cytokines and chemokines.OBJECTIVES:Here we use single-cell transcriptomic analyses to identify relevant immune cell and nonimmune cell populations for an in-depth characterization of cell types and inflammatory mediators in this disease.METHODS:Psoriasis skin lesions of eight patients are analyzed using single-cell technology. Data are further validated by in situ hybridization (ISH) of human tissues, serum analyses of human samples and tissues of a murine model of psoriasis, and by in vitro cell culture experiments.RESULTS:Several different immune-activated cell types with particular cytokine patterns are identified such as keratinocytes, T-helper cells, dendritic cells, macrophages, and fibroblasts. Apart from well-known factors, IL-14 (TXLNA), IL-18, and IL-32 are identified with prominent expression in individual cell types in psoriasis. The percentage of inflammatory cellular subtypes expressing IL-14, IL-18, and IL-32 was significantly higher in psoriatic skin compared with healthy control skin. These findings were confirmed by ISH of human skin samples, in a murine model of psoriasis, in human serum samples, and in in vitro experiments.CONCLUSIONS:Taken together, we provide a differentiated view of psoriasis immune-cell phenotypes that support the role of IL-14, IL-18, and IL-32 in psoriasis pathogenesis.

Obesity and high abdominal fat mass are risk factors for developing the chronic inflammatory skin disease psoriasis. They are associated with increased incidence, prevalence and severity of the disease. A positive effect of weight loss on psoriasis activity has been shown in several studies. Obesity-related factors such as the dysregulation of glucose and lipid metabolism, the activation of adipose tissue and resultant persistent low-grade inflammation have been discussed as links of obesity and inflammatory diseases. Recently, we demonstrated a critical role of free fatty acids (FFAs) in obesity-mediated exacerbation of psoriatic skin inflammation in both mice and humans. In the present study, we translated these findings into a therapeutic intervention. An open-label study focusing on the dietary reduction of FFAs was conducted in patients with mild-to-moderate plaque psoriasis, and disease severity and serum markers of inflammation were analyzed. Here, we show that such a dietary intervention improves psoriatic disease activity independently of weight loss. Diet-related metabolic changes, such as a reduction in saturated free fatty acids (SFAs), may thus be more important than weight loss itself. Moreover, dietary intervention inhibited the overall pro-inflammatory activation status in patients, as shown by analysis of serum inflammatory parameters using the Olink platform. From our pilot study, we conclude that dietary intervention focusing on SFA reduction has the capacity to reduce disease activity and general inflammatory status in psoriasis patients.

Nutrition, together with weight gain, alcohol consumption, physical activity, and other factors, is a risk factors for chronic inflammatory diseases [...]

Kidney fibrosis is a major culprit in the development and progression of chronic kidney disease (CKD), ultimately leading to the irreversible loss of organ function. Thymocyte differentiation antigen-1 (Thy-1) controls many core functions of fibroblasts relevant to fibrogenesis but is also found in a soluble form (sThy-1) in serum and urine. We investigated the association of sThy-1 with clinical parameters in patients with CKD receiving hemodialysis treatment compared to individuals with a preserved renal function. Furthermore, Thy-1 tissue expression was detected in a mouse model of diabetic CKD (eNOS−/−; db/db) and non-diabetic control mice (eNOS−/−). Serum and urinary sThy-1 concentrations significantly increased with deteriorating renal function, independent of the presence of diabetes. Serum creatinine is the major, independent, and inverse predictor of serum sThy-1 levels. Moreover, sThy-1 is not only predicted by markers of renal function but is also itself an independent and strong predictor of markers of renal function, i.e., serum creatinine. Mice with severe diabetic CKD show increased Thy-1 mRNA and protein expression in the kidney compared to control animals, as well as elevated urinary sThy-1 levels. Pro-fibrotic mediators, such as interleukin (IL)-4, IL-13, IL-6 and transforming growth factor β, increase Thy-1 gene expression and release of sThy-1 from fibroblasts. Our data underline the role of Thy-1 in the control of kidney fibrosis in CKD and raise the opportunity that Thy-1 may function as a renal antifibrotic factor.

ZusammenfassungDie Psoriasis ist eine chronisch-entzündliche Hauterkrankung. Der Entzündungsprozess betrifft nicht nur die Haut, sondern auch weitere Gewebe, wie Gelenke, Bänder und die Gefäße. Bei einem Großteil aller Psoriasis-Patienten bestehen Nebenerkrankungen wie Diabetes, Übergewicht, Fettstoffwechselstörungen und erhöhter Blutdruck. Der genaue pathophysiologische Zusammenhang zwischen Adipositas und Psoriasis ist nicht hinreichend geklärt. Es ist unklar, ob Psoriasis die Entstehung von Übergewicht begünstigt oder ob Adipositas die Entstehung einer Psoriasis durch einen chronisch pro-inflammatorischen Zustand fördert. Neuere Daten zeigen einen deutlichen Zusammenhang zwischen der Konzentration freier Fettsäuren und dem Ausprägungsgrad der Psoriasis. Eine Ernährungsumstellung und eine erhöhte körperliche Aktivität haben grundsätzlich eine positive Wirkung auf die Schuppenflechte und können das Ansprechen der verschiedenen Therapien erhöhen.

Psoriasis is a chronic inflammatory disease of the skin and joints associated with several comorbidities such as arthritis, diabetes mellitus and metabolic syndrome, including obesity, hypertension and dyslipidaemia, Crohn’s disease, uveitis and psychiatric and psychological diseases. Psoriasis has been described as an independent risk factor for cardiovascular diseases and thus patients with psoriasis should be monitored for the development of cardiovascular disease or metabolic syndrome. However, there is mounting evidence that psoriasis also affects the development of osteoporosis, an important metabolic disease with enormous clinical and socioeconomic impact. At present, there are still controversial opinions about the role of psoriasis in osteoporosis. A more in depth analysis of this phenomenon is of great importance for affected patients since, until now, bone metabolism is not routinely examined in psoriatic patients, which might have important long-term consequences for patients and the health system. In the present review, we summarize current knowledge on the impact of psoriatic inflammation on bone metabolism and osteoporosis.