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The extracellular matrix (ECM) is a dynamic structure that surrounds and anchors cellular components in tissues. In addition to functioning as a structural scaffold for cellular components, ECMs also regulate diverse biological functions, including cell adhesion, proliferation, differentiation, migration, cell-cell interactions, and intracellular signaling events. Dermal fibroblasts (dFBs), the major cellular source of skin ECM, develop from a common embryonic precursor to the highly heterogeneous subpopulations during development and adulthood. Upon injury, dFBs migrate into wound granulation tissue and transdifferentiate into myofibroblasts, which play a critical role in wound contraction and dermal ECM regeneration and deposition. In this review, we describe the plasticity of dFBs during development and wound healing and how various dFB-derived ECM molecules, including collagen, proteoglycans, glycosaminoglycans, fibrillins and matricellular proteins are expressed and regulated, and in turn how these ECM molecules play a role in regulating the function of dFBs and immune cells. Finally, we describe how dysregulation of ECM matrix is associated the pathogenesis of wound healing related skin diseases, including chronic wounds and keloid.

Zirconium-based porphyrinic MOFs (PMOFs, MOF = metal-organic framework) have gained considerable attention in the field of electric/thermo/photo-catalysis as heterogeneous single-site catalysts; however, the study on multisite synergistic catalysis of PMOFs are rare. Herein, we have successfully developed a highly regio- and stereo-selective synthetic method of (E)-β-vinylboronates through hydroboration of alkynes using PCN-222 (Cu, PCN = porous coordination network) as multifunctional heterogeneous catalyst. Compared with homogeneous catalytic system, high TOF value is achieved in the developed method, originating from the synergistic effect of central Cu(II) ions, N atoms of porphyrin rings and terminal –OH groups on Zr-nodes. Notably, density functional theory (DFT) study reveals that five-membered “Cu-N-B-C-C” ring is the key species responsible for the hydroboration process with specific selectivity.

Xin-Rui Liang,1,&ast; Wen-Hao Dong,1,&ast; Wen-Di Bi,2,&ast; Jing-Jing Li,1 Yan-Qiu Weng,3 Ling-Juan Zhang,3 Zhi-Yong Guo1 1Blood Purification Center, Changhai Hospital of Naval Medical University, Shanghai, People’s Republic of China; 2Brigade One Team 2, Basic Medical College, Naval Medical University, Shanghai, People’s Republic of China; 3Department of Nursing, Changhai Hospital of Naval Medical University, Shanghai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ling-Juan Zhang; Zhi-Yong Guo, Tel +86-21-31162989 ; +86-21-31161406, Fax +86-21-31161411, Email lindazhang_cn@126.com; drguozhiyong@163.comPurpose: To investigate the effect of iron-erythrocyte metabolism-related indexes on posttraumatic growth in MHD patients and their caregivers.Patients and Methods: A total of 170 pairs of MHD patients and their caregivers in Shanghai Changhai Hospital were enrolled in this research, which used sociodemographic characteristics, the Posttraumatic Growth Inventory (PTGI), the Perceived Social Support Scale (PSSS), and the Medical Coping Modes Questionnaire (MCMQ). The test data of 141 patients were retrieved from the hospital database.Results: Single-factor analysis showed that the PTGI score of patients with a mean corpuscular erythrocyte volume ≥ 100 fL was 85.4 ± 19.8 and those with a mean corpuscular erythrocyte volume lower than 100 fL were 70.6 ± 24.7; the PTGI scores of patients with reticulocytes > 1.5% were 68.8 ± 25.8, and those with reticulocytes < 1.5% were 78.4 ± 21.1; the PTGI scores of the caregivers whose serum iron was > 10.6 μmol /L were 78.2 ± 21.6, and those with serum iron < 10.6 μmol /L were 67.9 ± 22.8. The difference in MCMQ scores between the caregivers with transferrin saturation> 50% and with transferrin saturation< 20% was 18.9 ± 8.4. For the correlation test of serum iron, reticulocyte and PTGI scores for patients, the Pearson correlation coefficients were 0.239 and − 0.193, respectively, and the correlation test between erythrocyte distribution width SD and the score of caregivers MCMQ scale, the Pearson correlation coefficient was 0.225; p for all was< 0.05, with significant differences. There was no significant difference in the scores of different scales for total iron binding capacity (TIBC) at different levels.Conclusion: The indexes related to iron erythrocyte metabolism in MHD patients are correlated with ruminant meditation of patients and their caregivers and promotion of posttraumatic growth. Good nutritional status, adequate hematopoietic material, and normal erythrocyte count and function are also important for them.Keywords: caregiver, patient, PTGI, PSSS, MCMQ

Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and haveled the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation.We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.

Obesity is a growing epidemic worldwide, and it is also considered a major environmental factor contributing to the pathogenesis of inflammatory skin diseases, including psoriasis (PSO) and atopic dermatitis (AD). Moreover, obesity worsens the course and impairs the treatment response of these inflammatory skin diseases. Emerging evidence highlights that hypertrophied adipocytes and infiltrated immune cells secrete a variety of molecules, including fatty acids and adipokines, such as leptin, adiponectin, and a panel of cytokines/chemokines that modulate our immune system. In this review, we describe how adipose hypertrophy leads to a chronic low-grade inflammatory state in obesity and how obesity-related inflammatory factors are involved in the pathogenesis of PSO and/or AD. Finally, we discuss the potential role of antimicrobial peptides, mechanical stress and impairment of epidermal barrier function mediated by fast expansion, and dermal fat in modulating skin inflammation. Together, this review summarizes the current literature on how obesity is associated with the pathogenesis of PSO and AD, highlighting the potentially important but overlooked immunomodulatory role of adipose tissue in the skin.

A subset of dermal fibroblasts undergo rapid differentiation into adipocytes in response to infection and acutely produce the cathelicidin antimicrobial peptide gene Camp. Vitamin A and other retinoids inhibit adipogenesis yet can show benefit to skin disorders, such as cystic acne, that are exacerbated by bacteria. We observed that retinoids potently increase and sustain the expression of Camp in preadipocytes undergoing adipogenesis despite inhibition of markers of adipogenesis, such as Adipoq, Fabp4, and Rstn. Retinoids increase cathelicidin in both mouse and human preadipocytes, but this enhancement of antimicrobial peptide expression did not occur in keratinocytes or a sebocyte cell line. Preadipocytes undergoing adipogenesis more effectively inhibited growth of Staphylococcus aureus when exposed to retinoic acid. Whole transcriptome analysis identified hypoxia-inducible factor 1-α (HIF-1α) as a mechanism through which retinoids mediate this response. These observations uncouple the lipid accumulation element of adipogenesis from the innate immune response and uncover a mechanism, to our knowledge previously unsuspected, that may explain therapeutic benefits of retinoids in some skin disorders.

Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor-β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator-activated receptor-γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.

The UPF3B-dependent branch of the nonsense-mediated RNA decay (NMD) pathway is critical for human cognition. Here, we examined the role of UPF3B in the olfactory system. Single-cell RNA-sequencing (scRNA-seq) analysis demonstrated considerable heterogeneity of olfactory sensory neuron (OSN) cell populations in wild-type (WT) mice, and revealed that UPF3B loss influences specific subsets of these cell populations. UPF3B also regulates the expression of a large cadre of antimicrobial genes in OSNs, and promotes the selection of specific olfactory receptor (Olfr) genes for expression in mature OSNs (mOSNs). RNA-seq and Ribotag analyses identified classes of mRNAs expressed and translated at different levels in WT and Upf3b-null mOSNs. Integrating multiple computational approaches, UPF3B-dependent NMD target transcripts that are candidates to mediate the functions of NMD in mOSNs were identified in vivo. Together, our data provides a valuable resource for the olfactory field and insights into the roles of NMD in vivo.

The selective catalytic oxidation of alcohols is important both in laboratory and industrial production, and traditional oxidants cause environmentally lethal wastes. The development of dioxygen selective oxidation efficient has been pursued from atom-efficient, economic and environmental view of points. Using DFT calculation and ESI-MS experiments, we studied the activation of the Cu Cu bonded planar complex Cu 2 (ophen) 2 to dioxygen and the application of the dioxygen-copper system for the selective oxidation of alcohols. For practical application and green chemistry, this catalytic system avoided the use of a large excess of base and expensive nitroxyl derivatives. In the cycle of oxidation, two oxidative dehydrogenation processes featuring superoxide/peroxide ( I ) and hydroperoxide ( II ) occurred along with a series of conformational changes of the butterfly-like Cu-complex from stretched to folded to stretched. Additionally, we characterized the role of the water molecule as a proton mediator in the dioxygen-copper system.

In this study, we report that TIP39, a parathyroid hormone ligand family member that was recently identified to be expressed in the skin, can induce decorin expression and enhance wound repair. Topical treatment of mice with TIP39 accelerated wound repair, whereas TIP39-deficient mice had delayed repair that was associated with formation of abnormal collagen bundles. To study the potential mechanism responsible for the action of TIP39 in the dermis, fibroblasts were cultured in three-dimensional collagen gels, a process that results in enhanced decorin expression unless activated to differentiate to adipocytes, whereupon these cells reduce expression of several proteoglycans, including decorin. Small interfering RNA-mediated silencing of parathyroid hormone 2 receptor (PTH2R), the receptor for TIP39, suppressed the expression of extracellular matrix-related genes, including decorin, collagens, fibronectin, and matrix metalloproteases. Skin wounds in TIP39 –/– mice had decreased decorin expression, and addition of TIP39 to cultured fibroblasts induced decorin and increased phosphorylation and nuclear translocation of CREB. Fibroblasts differentiated to adipocytes and treated with TIP39 also showed increased decorin and production of chondroitin sulfate. Furthermore, the skin of PTH2R –/– mice showed abnormal extracellular matrix structure, decreased decorin expression, and skin hardness. Thus, the TIP39-PTH2R system appears to be a previously unrecognized mechanism for regulation of extracellular matrix formation and wound repair.

A novel coordination compound with the formula {[H3O]2[Mg(ABTC)(DMI)2]}n (1) (H4ABTC = 3,3′,5,5′-azobenzene-tetracarboxylic acid, DMI = 1,3-dimethy-2-imidazolidinone) as synthesized under solvothermal condition and characterized by thermogravimetric analysis, IR spectroscopy, X-ray powder diffraction and single crystal X-ray diffraction. Compound 1 features a novel 3-D anionic framework [Mg(ABTC)(DMI)2]n2n- constructed by linking adjacent 2-D layer with the phenyl rings of the ABTC4− ligands and can be classified as a (4,4)-connected PtS porous net; it also has highly heterogeneous catalysis activity for the cyanosilylation of carbonyl compounds at low loading (0.1 mol%) leading to up to 99% conversion of benzaldehyde under solvent-free conditions. When Mg-abtc MOF (1) was recycled five times, its catalytic activity remained with an inconspicuous decrease.

How obesity affects immune function is not well understood. Clinically, obesity is strongly associated with severe TH2 immunopathology1-3, though the physiological, cellular, and molecular underpinnings of this association remain obscure. Here, we demonstrate that obese mice are susceptible to severe atopic dermatitis (AD), a major manifestation of TH2 immunopathology and disease burden in humans4,5. Mechanistically, we show that dysregulation of the nuclear hormone receptor (NHR) PPARγ (peroxisome proliferator-activated receptor gamma) in T cells is a causal link between obesity and the increased TH2 immunopathology. We find that PPARγ oversees a cellular metabolic transcriptional program that restrains nuclear gene expression of the chief TH2 priming and effector cytokine interleukin-4 (IL-4). Accordingly, thiazolidinediones (TZDs), potent PPARγ agonists, robustly protect obese mice from TH2 immunopathology. Collectively, these findings establish PPARγ as a molecular link between obesity and TH2 immune homeostasis and identify TZDs as novel therapeutic candidates for TH2 immunopathology. Fundamentally, these findings demonstrate that shifting physiologic metabolic states can shape the tone of adaptive immune responses to modulate differential disease susceptibility.

Located at the skin surface, keratinocytes (KCs) are constantly exposed to external stimuli and are the first responders to invading pathogens and injury. Upon skin injury, activated KCs secrete an array of alarmin molecules, providing a rapid and specific innate immune response against danger signals. However, dysregulation of the innate immune response of KCs may lead to uncontrolled inflammation and psoriasis pathogenesis. Keratins (KRT) are the major structural intermediate filament proteins in KCs and are expressed in a highly specific pattern at different differentiation stages of KCs. While KRT14-KRT5 is restricted to basal proliferative KCs, and KRT10-KRT1 is restricted to suprabasal differentiated KCs in normal skin epidermis, the wound proximal KCs downregulate KRT10-K1 and upregulate KRT16/KRT17-KRT6 upon skin injury. Recent studies have recognized KRT6/16/17 as key early barrier alarmins and upregulation of these keratins alters proliferation, cell adhesion, migration and inflammatory features of KCs, contributing to hyperproliferation and innate immune activation of KCs in response to an epidermal barrier breach, followed by the autoimmune activation of T cells that drives psoriasis. Here, we have reviewed how keratins are dysregulated during skin injury, their roles in wound repairs and in initiating the innate immune system and the subsequent autoimmune amplification that arises in psoriasis.

SUMMARY Staphylococcus aureus is a major human bacterial pathogen responsible for deep tissue skin infections. Recent observations have suggested that rapid, localized digestion of hyaluronic acid in the extracellular matrix (ECM) of the dermis may influence bacterial invasion and tissue inflammation. In this study we find that cell migration-inducing protein (Cemip) is the major inducible gene responsible for hyaluronan catabolism in mice. Cemip−/− mice failed to digest hyaluronan and had significantly less evidence of infection after intradermal bacterial challenge by S. aureus. Stabilization of large-molecular-weight hyaluronan enabled increased expression of cathelicidin antimicrobial peptide (Camp) that was due in part to enhanced differentiation of preadipocytes to adipocytes, as seen histologically and by increased expression of Pref1, PPARg, and Adipoq. Cemip−/− mice challenged with S. aureus also had greater IL-6 expression and neutrophil infiltration. These observations describe a mechanism for hyaluronan in the dermal ECM to regulate tissue inflammation and host antimicrobial defense., In Brief In this paper, Dokoshi et al. describe how the mammalian hyaluronidase Cemip is induced in the dermis during S. aureus infection. Cemip digests hyaluronan in the skin to regulate reactive adipogenesis and subsequent antimicrobial activity and skin inflammation., Graphical Abstract

Epidermis, the outermost layer of the skin, plays a critical role as both a physical and immunological barrier protecting the internal tissues from external environmental insults, such as pathogenic bacteria, fungi, viruses, UV irradiation, and water loss. Epidermal keratinocytes (KC), the predominant cell type in the skin epidermis, are in the front line of skin defense. Here we describe methods to isolate and culture primary epidermal KC from neonatal and adult mouse skin and describe in vitro assays to study and characterize KC proliferation and differentiation and pro-inflammatory responses to viral products and UVB irradiation. These methods will be useful for researchers in the field of epidermal biology to set up in vitro assays to study the barrier and pro-inflammatory function of epidermal keratinocytes.

A domino silver-catalyzed intermolecularly nucleophilic addition of β-dicarbonyls to the isocyano group and cyclization of the imidoyl silver sequence was developed for the direct and efficient synthesis of indolin-3-ol derivatives. This domino transformation tolerates a range of readily available o-acyl arylisocyanides and 1,3-dicarbonyls under an operationally simple procedure. Triple roles of silver carbonate are demonstrated in this reaction: (1) activation of isocyano group, (2) formation of enolate, and (3) promotion the nucleophilic reactivity of imidoyl intermediate.

As the key defense molecules originally identified in Drosophila, Toll-like receptor (TLR) superfamily members play a fundamental role in detecting invading pathogens or damage and initiating the innate immune system of mammalian cells. The skin, the largest organ of the human body, protects the human body by providing a critical physical and immunological active multilayered barrier against invading pathogens and environmental factors. At the first line of defense, the skin is constantly exposed to pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and TLRs, expressed in a cell type-specific manner by various skin cells, serve as key molecules to recognize PAMPs and DAMPs and to initiate downstream innate immune host responses. While TLR-initiated inflammatory responses are necessary for pathogen clearance and tissue repair, aberrant activation of TLRs will exaggerate T cell-mediated autoimmune activation, leading to unwanted inflammation, and the development of several skin diseases, including psoriasis, atopic dermatitis, systemic lupus erythematosus, diabetic foot ulcers, fibrotic skin diseases, and skin cancers. Together, TLRs are at the interface between innate immunity and adaptive immunity. In this review, we will describe current understanding of the role of TLRs in skin defense and in the pathogenesis of psoriasis and atopic dermatitis, and we will also discuss the development and therapeutic effect of TLR-targeted therapies.

Epidermis, the outermost layer of the skin, plays a critical role as both a physical and immunological barrier protecting the internal tissues from external environmental insults, such as pathogenic bacteria, fungi, viruses, UV irradiation, and water loss. Epidermal keratinocytes (KC), the predominant cell type in the skin epidermis, are in the front line of skin defense. Here we describe methods to isolate and culture primary epidermal KC from neonatal and adult mouse skin and describe in vitro assays to study and characterize KC proliferation and differentiation and pro-inflammatory responses to viral products and UVB irradiation. These methods will be useful for researchers in the field of epidermal biology to set up in vitro assays to study the barrier and pro-inflammatory function of epidermal keratinocytes.

Nonalcoholic fatty liver disease (NAFLD) is characterized by high levels of nonesterified fatty acids (NEFA), inflammation, and hepatic steatosis. Inflammation plays a crucial role in the development of fatty liver. Resveratrol (RSV) supplement could improve inflammatory response and hepatic steatosis, whereas the underlying mechanism was not well understood. In this study, mice fed with high-fat diet (HFD) exhibited severe hepatic injury and high blood concentrations of the inflammatory cytokines TNF-α, IL-6, and IL-1β. Hepatic NF-κB inflammatory pathway was over-induced in HFD mice. In vitro, NEFA treatment further increased NF-κB pathway activation in mice hepatocytes, which then promoted the synthesis of inflammatory cytokines. Interestingly, RSV treatment significantly inhibited overactivation of NF-κB pathway and improved hepatic steatosis. Furthermore, RSV further increased the AMP-activated protein kinaseα (AMPKα) phosphorylation and sirtuin1 (SIRT1) protein levels to inhibit overactivation of NF-κB pathway induced by HFD or high levels of NEFA. AMPKα or SIRT1 inhibition significantly decreased the improvement effect of RSV on the NF-κB pathway induced by high levels of NEFA. Taken together, these findings indicate that RSV supplement decreases the inflammatory level and improves hepatic steatosis through activating AMPKα-SIRT1 pathway. Therefore, these data suggested an important clinical application of RSV in preventing NAFLD in humans.

An efficient catalytic system with dinuclear complex [Cu2(ophen)2] 1 and tetranuclear complex [Cu4(ophen)4(tp)] 2 as catalysts has been developed for the Glaser coupling reaction, which adopts environmentally friendly water as the solvent at room temperature under air/O2 atmosphere and avoids the utilization of any base. Satisfyingly, due to its poor solubility in common solvents, tetranuclear compound 2 served as a molecular heterogeneous catalyst and could be reused five times without loss of activity. Both catalysts could be prepared in high yield via simple hydrothermal reactions with cheap ligands, which in combination with the environmentally friendly water medium and mild catalytic reaction conditions makes the approach accord with the concept of green chemistry in the synthesis of 1,3-diynes.

An efficient method, tandem [3 + 2] cycloaddition–decarboxylation of α-keto acid and isocyanide promoted by copper salt, has been developed. Under oxidant-free conditions, a series monosubstituted oxazoles have been constructed. Different from the traditional application of α-oxo acids as acyl surrogates, the elegant approach herein ingeniously avoids consuming excess oxidants.

Antimicrobial peptides and proteins (AMPs) are a diverse class of naturally occurring molecules that are produced as a first line of defense by all multicellular organisms. These proteins can have broad activity to directly kill bacteria, yeasts, fungi, viruses and even cancer cells. Insects and plants primarily deploy AMPs as an antibiotic to protect against potential pathogenic microbes, but microbes also produce AMPs to defend their environmental niche. In higher eukaryotic organisms, AMPs can also be referred to as 'host defense peptides', emphasizing their additional immunomodulatory activities. These activities are diverse, specific to the type of AMP, and include a variety of cytokine and growth factor-like effects that are relevant to normal immune homeostasis. In some instances, the inappropriate expression of AMPs can also induce autoimmune diseases, thus further highlighting the importance of understanding these molecules and their complex activities. This Primer will provide an update of our current understanding of AMPs.

An efficient synthesis of biphenyls via three-coordinate planar dinuclear Cu 2 (ophen) 2 complex catalyzed homocoupling of arylboronic acids under air condition and in the condition of alkali-free was demonstrated. Uniquely, this catalyst shows high selectivity towards biphenyls when the reaction was conducted in aqueous solution, which is significantly different from selectivity towards phenols in related Cu-catalysts. Utilization of environmentally friendly water as main solvent, reaction at room temperature and in the absence of base, cheapness, low loading and easy bulk preparation of catalyst make it potential in green synthesis of biphenyls.

Background & Aims Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into collagen type I–producing myofibroblasts (activated HSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of activated HSCs/myofibroblasts into a quiescent-like state (inactivated HSCs). We aimed to identify molecular features of phenotypes of HSCs from mice and humans. Methods We performed studies with LratCre, Ets1-floxed, Nf1-floxed, Pparγ-floxed, Gata6-floxed, Rag2–/–γc–/–, and C57/Bl6 (control) mice. Some mice were given carbon tetrachloride (CCl4) to induce liver fibrosis, with or without a peroxisome proliferator-activated receptor–γ (PPARγ) agonist. Livers from mice were analyzed by immunohistochemistry. Quiescent, activated, and inactivated HSCs were isolated from livers of Col1α1YFP mice and analyzed by chromatin immunoprecipitation and sequencing. Human HSCs were isolated from livers denied for transplantation. We compared changes in gene expression patterns and epigenetic modifications (histone H3 lysine 4 dimethylation and histone H3 lysine 27 acetylation) in primary mouse and human HSCs. Transcription factors were knocked down with small hairpin RNAs in mouse HSCs. Results Motif enrichment identified E26 transcription-specific transcription factors (ETS) 1, ETS2, GATA4, GATA6, interferon regulatory factor (IRF) 1, and IRF2 transcription factors as regulators of the mouse and human HSC lineage. Small hairpin RNA-knockdown of these transcription factors resulted in increased expression of genes that promote fibrogenesis and inflammation, and loss of HSC phenotype. Disruption of Gata6 or Ets1, or Nf1 or Pparγ (which are regulated by ETS1), increased the severity of CCl4-induced liver fibrosis in mice compared to control mice. Only mice with disruption of Gata6 or Pparγ had defects in fibrosis resolution after CCl4 administration was stopped, associated with persistent activation of HSCs. Administration of a PPARγ agonist accelerated regression of liver fibrosis after CCl4 administration in control mice but not in mice with disruption of Pparγ. Conclusions Phenotypes of HSCs from humans and mice are regulated by transcription factors, including ETS1, ETS2, GATA4, GATA6, IRF1, and IRF2. Activated mouse and human HSCs can revert to a quiescent-like, inactivated phenotype. We found GATA6 and PPARγ to be required for inactivation of human HSCs and regression of liver fibrosis in mice.

In this study we evaluated the role of hyaluronan (HA) in reactive adipogenesis, a local expansion of preadipocytes that provides host defense by release of antimicrobial peptides. We observed that HA accumulated during maturation of adipocytes in vitro and was associated with increased expression of preadipocyte factor 1, zinc finger protein 423, and early B cell factor 1. Although HA is normally abundant in the extracellular matrix, a further increase in HA staining occurred in mice at sites of reactive adipogenesis following injury of colon by dextran sodium sulfate or injury of skin from infection with Staphylococcus aureus. HA also abundantly accumulated around adipocytes seen in the colons of patients with inflammatory bowel disease. This HA was necessary for adipocyte maturation because digestion of HA by administration of soluble hyaluronidase or transgenic expression of hyaluronidase 1 inhibited adipogenesis in vitro and in vivo. Furthermore, hyaluronidase also suppressed inflammation of both skin and colon and decreased antimicrobial peptide expression by developing preadipocytes. This resulted in increased bacterial transit across the epithelial barrier despite decreased tissue injury from inflammation. These observations suggest HA plays an important role in reactive adipogenesis and host defense after injury.

Dermal white adipose tissue is a unique layer of adipocytes within the reticular dermis of the skin. Recently, several nonmetabolic activities have been discovered for dWAT and its fibroblast precursors. These functions include antimicrobial defense and roles in hair cycling, wound healing, and thermogenesis. In this review, we discuss recent progress in understanding the role of dermal white adipose tissue in immunity, both as an innate antimicrobial cell type and as an indirect communicator with other cutaneous immunocytes to enhance defense and potentially contribute to inflammatory disease.

Under homeostatic conditions the release of self-RNA from dying cells does not promote inflammation. However, following injury or inflammatory skin diseases such as psoriasis and rosacea, expression of the cathelicidin antimicrobial peptide LL37 breaks tolerance to self-nucleic acids and triggers inflammation. Here we report that LL37 enables keratinocytes and macrophages to recognize self-non-coding U1 RNA by facilitating binding to cell surface scavenger receptors that enable recognition by nucleic acid pattern recognition receptors within the cell. The interaction of LL37 with scavenger receptors was confirmed in human psoriatic skin, and the ability of LL37 to stimulate expression of interleukin-6 and interferon-β1 was dependent on a 3-way binding interaction with scavenger receptors and subsequent clathrin-mediated endocytosis. These results demonstrate that the inflammatory activity of LL37 is mediated by a cell-surface-dependent interaction and provides important new insight into mechanisms that drive auto-inflammatory responses in the skin.