Mechanisms Of Tissue Remodeling Research Articles

Bioactive scaffolds for tissue engineering: A review of decellularized extracellular matrix applications and innovations

AbstractDecellularized extracellular matrix (dECM) offers a three‐dimensional, non‐immunogenic scaffold, enriched with bioactive components, making it a suitable candidate for tissue regeneration. Although dECM‐based scaffolds have been successfully implemented in preclinical and clinical settings within tissue engineering and regenerative medicine, the mechanisms of tissue remodeling and functional restoration are not fully understood. This review critically assesses the state‐of‐the‐art in dECM scaffolds, including decellularization techniques for various tissues, quality control and cross‐linking. It highlights the functional properties of dECM components and their latest applications in multiorgan tissue engineering and biomedicine. Additionally, the review addresses current challenges and limitations of decellularized scaffolds and offers perspectives on future directions in the field.

Neuronally differentiated macula densa cells regulate tissue remodeling and regeneration in the kidney.

Tissue regeneration is limited in several organs including the kidney, contributing to the high prevalence of kidney disease globally. However, evolutionary and physiological adaptive responses and the presence of renal progenitor cells suggest existing remodeling capacity. This study uncovered endogenous tissue remodeling mechanisms in the kidney that were activated by the loss of body fluid and salt and regulated by a unique niche of a minority renal cell type called the macula densa (MD). Here we identified neuronal differentiation features of MD cells that sense the local and systemic environment, secrete angiogenic, growth and extracellular matrix remodeling factors, cytokines and chemokines, and control resident progenitor cells. Serial intravital imaging, MD nerve growth factor receptor and Wnt mouse models and transcriptome analysis revealed cellular and molecular mechanisms of these MD functions. Human and therapeutic translation studies illustrated the clinical potential of MD factors including CCN1 as a urinary biomarker and therapeutic target in chronic kidney disease. The concept that a neuronally differentiated key sensory and regulatory cell type responding to organ-specific physiological inputs controls local progenitors to remodel or repair tissues may be applicable to other organs and diverse tissue regenerative therapeutic strategies.

Ganglioside GD3 Regulates Inflammation and Epithelial-to-Mesenchymal Transition in Human Nasal Epithelial Cells.

Chronic sinusitis with nasal polyps (CRSwNP) is one of the most common chronic inflammatory diseases, and involves tissue remodeling. One of the key mechanisms of tissue remodeling is the epithelial-mesenchymal transition (EMT), which also represents one of the pathophysiological processes of CRS observed in CRSwNP tissues. To date, many transcription factors and forms of extracellular stimulation have been found to regulate the EMT process. However, it is not known whether gangliosides, which are the central molecules of plasma membranes, involved in regulating signal transmission pathways, are involved in the EMT process. Therefore, we aimed to determine the role of gangliosides in the EMT process. First, we confirmed that N-cadherin, which is a known mesenchymal marker, and ganglioside GD3 were specifically expressed in CRSwNP_NP tissues. Subsequently, we investigated whether the administration of TNF-α to human nasal epithelial cells (hNECs) resulted in the upregulation of ganglioside GD3 and its synthesizing enzyme, ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialytransferase 1 (ST8Sia1), and the consequently promoted inflammatory processes. Additionally, the expression of N-cadherin, Zinc finger protein SNAI2 (SLUG), and matrix metallopeptidase 9 (MMP-9) were elevated, but that of E-cadherin, which is known to be epithelial, was reduced. Moreover, the inhibition of ganglioside GD3 expression by the siRNA or exogenous treatment of neuraminidase 3 (NEU 3) led to the suppression of inflammation and EMT. These results suggest that gangliosides may play an important role in prevention and therapy for inflammation and EMT.

Pituitary Tumor-Transforming Gene 1/Delta like Non-Canonical Notch Ligand 1 Signaling in Chronic Liver Diseases

The management of chronic liver diseases (CLDs) remains a challenge, and identifying effective treatments is a major unmet medical need. In the current review we focus on the pituitary tumor transforming gene (PTTG1)/delta like non-canonical notch ligand 1 (DLK1) axis as a potential therapeutic target to attenuate the progression of these pathological conditions. PTTG1 is a proto-oncogene involved in proliferation and metabolism. PTTG1 expression has been related to inflammation, angiogenesis, and fibrogenesis in cancer and experimental fibrosis. On the other hand, DLK1 has been identified as one of the most abundantly expressed PTTG1 targets in adipose tissue and has shown to contribute to hepatic fibrosis by promoting the activation of hepatic stellate cells. Here, we extensively analyze the increasing amount of information pointing to the PTTG1/DLK1 signaling pathway as an important player in the regulation of these disturbances. These data prompted us to hypothesize that activation of the PTTG1/DLK1 axis is a key factor upregulating the tissue remodeling mechanisms characteristic of CLDs. Therefore, disruption of this signaling pathway could be useful in the therapeutic management of CLDs.

An EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling afterinjury.

Unveiling the molecular mechanisms of tissue remodelling following injury is imperative to elucidate its regenerative capacity and aberrant repair in disease. Using different omics approaches, we identified enhancer of zester homolog 2 (EZH2) as a key regulator of fibrosis in injured lung epithelium. Epithelial injury drives an enrichment of nuclear transforming growth factor‐β‐activated kinase 1 (TAK1) that mediates EZH2 phosphorylation to facilitate its liberation from polycomb repressive complex 2 (PRC2). This process results in the establishment of a transcriptional complex of EZH2, RNA‐polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial repair programmes. The liberation of EZH2 from PRC2 is accompanied by an EZH2‐EZH1 switch to preserve H3K27me3 deposition at non‐target genes. Loss of epithelial TAK1, EZH2 or blocking nuclear actin influx attenuates the fibrotic cascade and restores respiratory homeostasis. Accordingly, EZH2 inhibition significantly improves outcomes in a pulmonary fibrosis mouse model. Our results reveal an important non‐canonical function of EZH2, paving the way for new therapeutic interventions in fibrotic lung diseases.

Regulatory properties of vitronectin and its glycosylation in collagen fibril formation and collagen-degrading enzyme cathepsin K activity

Vitronectin (VN) is a glycoprotein found in extracellular matrix and blood. Collagen, a major extracellular matrix component in mammals, is degraded by cathepsin K (CatK), which is essential for bone resorption under acidic conditions. The relationship between VN and cathepsins has been unclear. We discovered that VN promoted collagen fibril formation and inhibited CatK activity, and observed its activation in vitro. VN accelerated collagen fibril formation at neutral pH. Collagen fibers formed with VN were in close contact with each other and appeared as scattered flat masses in scanning electron microscopy images. VN formed collagen fibers with high acid solubility and significantly inhibited CatK; the IC50 was 8.1–16.6 nM and competitive, almost the same as those of human and porcine VNs. VN inhibited the autoprocessing of inactive pro-CatK from active CatK. DeN-glycosylation of VN attenuated the inhibitory effects of CatK and its autoprocessing by VN, but had little effect on acid solubilization of collagen and VN degradation via CatK. CatK inhibition is an attractive treatment approach for osteoporosis and osteoarthritis. These findings suggest that glycosylated VN is a potential biological candidate for CatK inhibition and may help to understand the molecular mechanisms of tissue re-modeling.

Markers of tissue remodeling and inflammation in the white and brown adipose tissues of a model hibernator

The thirteen-lined ground squirrel is a model fat-storing hibernator that nearly doubles its weight in the fall to fuel metabolism with triglycerides throughout the winter months. Hibernator brown and white adipose tissue (BAT, WAT) are important to study in terms of their inflammatory profile and tissue remodeling mechanisms since controlled and natural regulation of these processes could inform new pharmacological interventions that limit oxidative stress and inflammation in the adipose tissues of humans suffering from obesity, promote non-shivering thermogenesis-mediated weight loss, or prevent tissue damage in transplantable organs emerging from cold-storage. Thus, markers of inflammation like cytokines and soluble receptors and tissue remodeling proteins such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were investigated in normothermic, torpid, and arousing ground squirrels. Multiplex protein assays and western blotting revealed fewer changes in WAT compared to BAT. Pro-inflammatory IL-1α levels increased during torpor and soluble epidermal growth factor receptor protein levels increased during arousal in BAT. Given their known roles in other model systems, these proteins could regulate processes like adipogenesis, lipid catabolism, or cell motility. Decreased TIMP2 levels combined with maintained MMP2 or MMP3 protein levels suggested that BAT may avoid tissue remodeling until arousal. No changes in WAT inflammatory cytokines or soluble receptors as well as decreased MMP2 levels during torpor and arousal suggested inflammation and modification to the extracellular matrix is likely suppressed in WAT. This study emphasizes the fat-but-fit nature of the hibernating ground squirrel and the ability of its fat stores to suppress inflammation.

Palatal expansion and relapse in rats: A histologic and immunohistochemical study

Rapid palatal expansion is an effective intervention for correcting transverse maxillary deficiency in growing patients. However, relapse after treatment is often observed, and the mechanisms of tissue remodeling during expansion and relapse remain unclear. This study aimed to gain insight into such a mechanism. A total of 24 5-week-old male Wistar rats were randomly divided into either the expansion or sham device (control) group. Each rat underwent 7days of expansion and 7days of relapse. The width of the dental arch, palatal bone, and suture, as well as the angle of the teeth, were measured. Tissue remodeling in the midpalatal suture was examined using microcomputed tomography and histologic and immunohistochemical analyses. The mechanical expansion force caused an increase in arch width, which relapsed after the removal of force. Bilateral tilting of the teeth and midpalatal suture expansion contributed to the widening of the maxillary arch, and only the relapse of the palatal bone width was observed. Histochemical staining showed that suture tissue remodeling was activated by mechanical force in the expansion group and reverted to the level of the control group after relapse. Immunohistochemistry staining revealed that the expression of cathepsin K, osteocalcin, and collagen type I was higher in the expansion group than that in the control group on day 7; however, the difference dissipated by day14. The expansion force stimulated osteogenic activity in the midpalatal suture area. After removal of the expansion force, tissue remodeling went back to the normal level.

Autophagy in animal development.

Macroautophagy (autophagy) delivers intracellular constituents to the lysosome to promote catabolism. During development in multiple organisms, autophagy mediates various cellular processes, including survival during starvation, programmed cell death, phagocytosis, organelle elimination, and miRNA regulation. Our current understanding of autophagy has been enhanced by developmental biology research during the last quarter of a century. Through experiments that focus on animal development, fundamental mechanisms that control autophagy and that contribute to disease were elucidated. Studies in embryos revealed specific autophagy molecules that mediate the removal of paternally derived mitochondria, and identified autophagy components that clear protein aggregates during development. Importantly, defects in mtDNA inheritance, or removal of paternal mtDNA via mitochondrial autophagy, can contribute to mitochondrial-associated disease. In addition, impairment of the clearance of protein aggregates by autophagy underlies neurodegenerative diseases. Experiments in multiple organisms also reveal conserved mechanisms of tissue remodeling that rely on the cooperation between autophagy and apoptosis to clear cell corpses, and defects in autophagy and apoptotic cell clearance can contribute to inflammation and autoimmunity. Here we provide an overview of key developmental processes that are mediated by autophagy in multiple animals.

Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-β as Tissue Remodelling Players.

A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-β are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-β and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.

Skin Grafting in Xenopus laevis: A Technique for Assessing Development and Immunological Disparity.

Skin grafting in the amphibian Xenopus laevis has been used to detect not only allogeneic antigens that differ by minor H antigens or by one MHC haplotype, but also to detect ontogeny-specific antigens (including both emerging adult- and disappearing larval-specific) during metamorphosis. To understand the mechanisms underlying allogeneic tolerance or immune responses against larval- and/or adult-specific antigens, a complete MHC homozygous, inbred strain is the most appropriate experimental model. The inbred J strain established in Japan is used here. Owing to complete histocompatibility, the inbred J strain shows no grafted skin rejection among the same strain of adult frogs, and its genuine homozygosity was reconfirmed by genomic sequence analysis in 2016. Therefore, the J strain enables immunologists and embryologists to understand evolutionary processes as well as immunological events and tissue remodeling mechanisms present during development. Furthermore, an F1 hybrid between the J strain and a GFP-labeled transgenic line is available from our laboratory and can be used as a model for long-term cell tracking. This protocol explains the methodology for skin grafting in X. laevis to determine immunological discrepancies between the host and donor. It is also possible to trace cell and tissue fates in the hosts during early embryogenesis and during complete development from larvae to adults, which is extremely difficult to perform using other species.

Novel fluorescence techniques to quantitate renal cell biology.

Fluorescence microscopy techniques are powerful tools to study tissue dynamics, cellular function and biology both in vivo and in vitro. These tools allow for functional assessment and quantification along with qualitative analysis, thus providing a comprehensive understanding of various cellular processes under normal physiological and disease conditions. The main focus of this chapter is the recently developed method of serial intravital multiphoton microscopy that has helped shed light on the dynamic alterations of the spatial distribution and fate of single renal cells or cell populations and their migration patterns in the same tissue region over several days in response to various stimuli within the living kidney. This technique is very useful for studying in vivo the molecular and cellular mechanisms of tissue remodeling and repair after injury. In addition, complementary in vitro imaging tools are also described and discussed, like tissue clearing techniques and protein synthesis measurement in tissues in situ that provide an in depth assessment of changes at the cellular level. Thus, these novel fluorescence techniques can be effectively leveraged for different tissue types, experimental conditions as well as disease models to improve our understanding of renal cell biology.

Selective proteolysis by matrix metalloproteinases of photo-oxidised dermal extracellular matrix proteins

Photodamage in chronically sun-exposed skin manifests clinically as deep wrinkles and histologically as extensive remodelling of the dermal extracellular matrix (ECM) and in particular, the elastic fibre system. We have shown previously that loss of fibrillin microfibrils, a key elastic fibre component, is a hallmark of early photodamage and that these ECM assemblies are susceptible in vitro to physiologically attainable doses of ultraviolet radiation (UVR). Here, we test the hypotheses that UVR-mediated photo-oxidation is the primary driver of fibrillin microfibril and fibronectin degradation and that prior UVR exposure will enhance the subsequent proteolytic activity of UVR-upregulated matrix metalloproteinases (MMPs).We confirmed that UVB (280-315 nm) irradiation in vitro induced structural changes to both fibrillin microfibrils and fibronectin and these changes were largely reactive oxygen species (ROS)-driven, with increased ROS lifetime (D2O) enhancing protein damage and depleted O2 conditions abrogating it. Furthermore, we show that although exposure to UVR alone increased microfibril structural heterogeneity, exposure to purified MMPs (1, −3, −7 and − 9) alone had minimal effect on microfibril bead-to-bead periodicity; however, microfibril suspensions exposed to UVR and then MMPs were more structurally homogenous. In contrast, the susceptibly of fibronectin to proteases was unaffected by prior UVR exposure. These observations suggest that both direct photon absorption and indirect production of ROS are important mediators of ECM remodelling in photodamage. We also show that fibrillin microfibrils are relatively resistant to proteolysis by MMPs −1, −3, −7 and − 9 but that these MMPs may selectively remove damaged microfibril assemblies. These latter observations have implications for predicting the mechanisms of tissue remodelling and targeted repair.

Assessment of Ablative Fractional CO2 Laser and Er:YAG Laser to Treat Hypertrophic Scars in a Red Duroc Pig Model.

Hypertrophic scarring is a fibroproliferative process that occurs following a third-degree dermal burn injury, producing significant morbidity due to persistent pain, itching, cosmetic disfigurement, and loss of function due to contractures. Ablative fractional lasers have emerged clinically as a fundamental or standard therapeutic modality for hypertrophic burn scars. Yet the examination of their histopathological and biochemical mechanisms of tissue remodeling and comparison among different laser types has been lacking. In addition, deficiency of a relevant animal model limits our ability to gain a better understanding of hypertrophic scar pathophysiology. To evaluate the effect of ablative fractional lasers on hypertrophic third-degree burn scars, we have developed an in vivo Red Duroc porcine model. Third-degree burn wounds were created on the backs of animals, and burn scars were allowed to develop for 70 days before treatment. Scars received treatment with either CO2 or erbium: yttrium aluminum garnet (YAG) ablative fractional lasers. Here, we describe the effect of both lasers on hypertrophic third-degree burn scars in Red Duroc pigs. In this report, we found that Er:YAG has improved outcomes versus fractional CO2. Molecular changes noted in the areas of dermal remodeling indicated that matrix metalloproteinase 2, matrix metalloproteinase 9, and Decorin may play a role in this dermal remodeling and account for the enhanced effect of the Er:YAG laser. We have demonstrated that ablative fractional laser treatment of burn scars can lead to favorable clinical, histological, and molecular changes. This study provides support that hypertrophic third-degree burn scars can be modified by fractional laser treatment.

Fibrinogen scaffolds with immunomodulatory properties promote invivo bone regeneration.

The hypothesis behind this work is that fibrinogen (Fg), classically considered a pro-inflammatory protein, can promote bone repair/regeneration. Injury and biomaterial implantation naturally lead to an inflammatory response, which should be under control, but not necessarily minimized. Herein, porous scaffolds entirely constituted of Fg (Fg-3D) were implanted in a femoral rat bone defect and investigated at two important time points, addressing the bone regenerative process and the local and systemic immune responses, both crucial to elucidate the mechanisms of tissue remodelling. Fg-3D led to early infiltration of granulation tissue (6 days post-implantation), followed by bone defect closure, including periosteum repair (8 weeks post-injury). In the acute inflammatory phase (6 days) local gene expression analysis revealed significant increases of pro-inflammatory cytokines IL-6 and IL-8, when compared with non-operated animals. This correlated with modified proportions of systemic immune cell populations, namely increased T cells and decreased B, NK and NKT lymphocytes and myeloid cell, including the Mac-1+ (CD18+/CD11b+) subpopulation. At 8 weeks, Fg-3D led to decreased plasma levels of IL-1β and increased TGF-β1. Thus, our data supports the hypothesis, establishing a link between bone repair induced by Fg-3D and the immune response. In this sense, Fg-3D scaffolds may be considered immunomodulatory biomaterials.

Gelatin-based Hydrogel Degradation and Tissue Interaction in vivo: Insights from Multimodal Preclinical Imaging in Immunocompetent Nude Mice.

Hydrogels based on gelatin have evolved as promising multifunctional biomaterials. Gelatin is crosslinked with lysine diisocyanate ethyl ester (LDI) and the molar ratio of gelatin and LDI in the starting material mixture determines elastic properties of the resulting hydrogel. In order to investigate the clinical potential of these biopolymers, hydrogels with different ratios of gelatin and diisocyanate (3-fold (G10_LNCO3) and 8-fold (G10_LNCO8) molar excess of isocyanate groups) were subcutaneously implanted in mice (uni- or bilateral implantation). Degradation and biomaterial-tissue-interaction were investigated in vivo (MRI, optical imaging, PET) and ex vivo (autoradiography, histology, serum analysis). Multimodal imaging revealed that the number of covalent net points correlates well with degradation time, which allows for targeted modification of hydrogels based on properties of the tissue to be replaced. Importantly, the degradation time was also dependent on the number of implants per animal. Despite local mechanisms of tissue remodeling no adverse tissue responses could be observed neither locally nor systemically. Finally, this preclinical investigation in immunocompetent mice clearly demonstrated a complete restoration of the original healthy tissue.

Surgical Injury to the Mouse Pancreas through Ligation of the Pancreatic Duct as a Model for Endocrine and Exocrine Reprogramming and Proliferation.

Expansion of pancreatic beta cells in vivo or ex vivo, or generation of beta cells by differentiation from an embryonic or adult stem cell, can provide new expandable sources of beta cells to alleviate the donor scarcity in human islet transplantation as therapy for diabetes. Although recent advances have been made towards this aim, mechanisms that regulate beta cell expansion and differentiation from a stem/progenitor cell remain to be characterized. Here, we describe a protocol for an injury model in the adult mouse pancreas that can function as a tool to study mechanisms of tissue remodeling and beta cell proliferation and differentiation. Partial duct ligation (PDL) is an experimentally induced injury of the rodent pancreas involving surgical ligation of the main pancreatic duct resulting in an obstruction of drainage of exocrine products out of the tail region of the pancreas. The inflicted damage induces acinar atrophy, immune cell infiltration and severe tissue remodeling. We have previously reported the activation of Neurogenin (Ngn) 3 expressing endogenous progenitor-like cells and an increase in beta cell proliferation after PDL. Therefore, PDL provides a basis to study signals involved in beta cell dynamics and the properties of an endocrine progenitor in adult pancreas. Since, it still remains largely unclear, which factors and pathways contribute to beta cell neogenesis and proliferation in PDL, a standardized protocol for PDL will allow for comparison across laboratories.

Partial duct ligation: β-cell proliferation and beyond.

Experimentally induced injury is an established strategy for studying mechanisms of tissue remodeling with the final goal of developing new regenerative therapies. Under normal physiological conditions, proliferation and differentiation of progenitor cells, including even canonical stem cell−like activity, can be stimulated in tissues, such as brain and liver, that have a low cellular turnover rate (1,2). The presence of stem/progenitor cells in the pancreas could be relevant to normal homeostatic maintenance of various cell types in this organ, such as endocrine hormone−expressing cells, enzyme-secreting acinar cells, and the less secretory exocrine duct cells. Further, pancreatic stem/progenitor cells may be a possible source for replenishing cells destroyed by autoimmune disease or other stressors. We speculate that proliferative progenitors might be isolated, expanded, and differentiated in vitro to alleviate the donor scarcity in human islet transplantation and may therefore be developed as a therapy for diabetes. However, the existence and exact location of adult stem- or progenitor-like cells that can give rise to functional β-cells is highly controversial. This Perspective focuses on findings from a severe insult model (partial duct ligation [PDL]) with a long history (3). PDL received renewed attention when a 2008 study combined it with genetic reporter strategies now possible in mice to try to identify and isolate cells acting as β-cell progenitors (4). In vivo β-cell neogenesis under PDL was recently substantiated (5,6). Because the outcomes from this technique appear to vary across laboratories, we summarize and discuss some of the reported discrepancies to help identify current limitations and pitfalls of this model as well as opportunities for forward progress. The mechanisms leading to replacement of the endogenous β-cell pool have been studied under several cell ablation paradigms to test for the existence and type of cells in the adult mouse pancreas that are …

Eosinophils and allergy

The results of the modern scientific researches regarding a new view on a role of eosinophils in allergy as multifunctional cells are colligated in the review. First of all, it concerns participation of eosinophils in regulation of Th2type of the immune response, in formation of allergic inflammation and tissue damage. Their role in outcome of these processes - reparation or chronization of illness, including mechanisms of tissue remodeling is also very important.

The chemokine receptor CCR3 participates in tissue remodeling during atopic skin inflammation

BackgroundRecent studies provided insights into the recruitment and activation pathways of leukocytes in atopic dermatitis, however, the underlying mechanisms of tissue remodeling in atopic skin inflammation remain elusive. ObjectiveTo identify chemokine-mediated communication pathways regulating tissue remodeling during atopic skin inflammation. MethodsAnalysis of the chemokine receptor repertoire of human dermal fibroblasts using flow cytometry and immunofluorescence. Quantitative real-time polymerase chain reaction and immunohistochemical analyses of chemokine expression in atopic vs. non-atopic skin inflammation. Investigation of the function of chemokine receptor CCR3 on human dermal fibroblasts through determining intracellular Ca2+ mobilization, cell proliferation, migration, and repair capacity. ResultsAnalyses on human dermal fibroblasts showed abundant expression of the chemokine receptor CCR3 in vitro and in vivo. Among its corresponding ligands (CCL5, CCL8, CCL11, CCL24 and CCL26) CCL26 demonstrated a significant and specific up-regulation in atopic when compared to psoriatic skin inflammation. In vivo, epidermal keratinocytes showed most abundant CCL26 protein expression in lesional atopic skin. In structural cells of the skin, TH2-cytokines such as IL-4 and IL-13 were dominant inducers of CCL26 expression. In dermal fibroblasts, CCL26 induced CCR3 signaling resulting in intracellular Ca2+ mobilization, as well as enhanced fibroblast migration and repair capacity, but no proliferation. ConclusionTaken together, findings of the present study suggest that chemokine-driven communication pathways from the epidermis to the dermis may modulate tissue remodeling in atopic skin inflammation.