In This Issue

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Schlafen-8 is essential for lymphatic endothelial cell activation in experimental autoimmune encephalomyelitis

Abstract

Schlafen-8 (Slfn8) is a member of the Schlafen family of proteins, which harbor helicase domains and are induced by LPS and interferons. It has been reported that the Schlafen family are involved in various cellular functions, including proliferation, differentiation and regulation of virus replication. Slfn8 has been implicated in T-cell differentiation in the thymus. However, the roles of Slfn8 in the immune system remains unclear. In this study, we generated Slfn8 knockout mice (Slfn8^−/−) and investigated the immunological role of Slfn8 using the T-cell-mediated autoimmune model experimental autoimmune encephalomyelitis (EAE). We found that the clinical score was reduced in Slfn8^−/− mice. IL-6 and IL-17A cytokine production, which are associated with EAE onset and progression, were decreased in the lymph nodes of Slfn8^−/− mice. Immune cell populations in Slfn8^−/− mice, including macrophages, neutrophils, T cells and B cells, did not reveal significant differences compared with wild-type mice. In vitro activation of Slfn8^−/− T cells in response to TCR stimulation also did not reveal significant differences. To confirm the involvement of non-hematopoietic cells, we isolated CD45⁻ CD31⁺ endothelial cells and CD45⁻CD31⁻ gp38⁺ fibroblastic reticular cells by FACS sorting. We showed that the levels of IL-6 and Slfn8 mRNA in CD45⁻ CD31⁺ endothelial cells were increased after EAE induction. In contrast, the level of IL-6 mRNA after EAE induction was markedly decreased in CD31⁺ endothelial cells from Slfn8^−/− mice. These results indicate that Slfn8 may play a role in EAE by regulating inflammation in endothelial cells.

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Mechanisms controlling nucleic acid-sensing Toll-like receptors

Abstract

Nucleic acid (NA)-sensing Toll-like receptors (TLRs) respond to DNA/RNA derived from pathogens and dead cells. Structural studies have revealed a variety of molecular mechanisms by which TLRs sense NAs. Double-stranded RNA and single-stranded DNA directly bind to TLR3 and TLR9, respectively, whereas TLR7 and TLR8 bind to nucleosides and oligoribonucleotides derived from RNAs. Activation of ligand-bound TLRs is influenced by the functional status of TLRs. Proteolytic cleavage of NA-sensing TLRs enables ligand-dependent TLR dimerization. Trafficking of ligand-activated TLRs in endosomal and lysosomal compartments is requisite for production of type I interferons. Activation of NA-sensing TLRs is required for the control of viruses such as herpes simplex virus and endogenous retroviruses. On the other hand, excessive activation of NA-sensing TLRs drives disease progression in a variety of inflammatory diseases including systemic lupus erythematosus, heart failure, arthritis and non-alcoholic steatohepatitis. NA-sensing TLRs are targets for therapeutic intervention in these diseases. We here focus on our recent progresses in our understanding of NA-sensing TLRs.

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Single blood transfusion induces the production of donor-specific alloantibodies and regulatory T cells mainly in the spleen

Abstract

Donor-specific blood transfusion is known to induce alloresponses and lead to immunosuppression. We examined their underlying mechanisms by employing fully allogeneic rat combinations. Transfused recipients efficiently produced alloantibodies of the IgM and IgG subclasses directed against donor class I MHC. The recipients exhibited active expansion of CD4⁺ T cells and CD4⁺FOXP3⁺ regulatory T cells (T_reg cells), followed by CD45R⁺ B cells and IgM⁺ or IgG subclass⁺ antibody-forming cells mainly in the spleen. From 1.5 days, the resident MHCII⁺CD103⁺ dendritic cells (DCs) in the splenic T-cell area, periarterial lymphocyte sheath, formed clusters with recipient BrdU⁺ or 5-ethynyl-2′-deoxyuridine⁺ cells, from which the proliferative response of CD4⁺ T cells originated peaking at 3–4 days. Transfusion-induced antibodies had donor passenger cell-depleting activity in vitro and in vivo and could suppress acute GvH disease caused by donor T cells. Furthermore, T_reg cells significantly suppressed mixed leukocyte reactions in a donor-specific manner. In conclusion, single blood transfusion efficiently induced a helper T-cell-dependent anti-donor class I MHC antibody-forming cell response with immunoglobulin class switching, and a donor-specific T_reg cell response mainly in the spleen, probably by way of the indirect allorecognition via resident DCs. These antibodies and T_reg cells may be involved, at least partly, in the donor-specific transfusion-induced suppression of allograft rejection.

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Oxidative burst and Dectin-1-triggered phagocytosis affected by norepinephrine and endocannabinoids: implications for fungal clearance under stress

Abstract

A prolonged stress burden is known to hamper the efficiency of both the innate and the adaptive immune systems and to attenuate the stress responses by the catecholaminergic and endocannabinoid (EC) systems. Key mechanisms of innate immunity are the eradication of pathogens through phagocytosis and the respiratory burst. We tested the concentration-dependent, spontaneous and stimulated (via TNFα and N-formylmethionine-leucyl-phenylalanine) release of reactive oxygen species (ROS) by human polymorphonuclear leukocytes (PMNs) in vitro in response to norepinephrine (NE) and AM1241, a pharmacological ligand for the EC receptor CB₂. We evaluated phagocytosis of Dectin-1 ligating zymosan particles and tested the cytokine response against Candida antigen in an in vitro cytokine release assay. Increasing concentrations of NE did not affect phagocytosis, yet stimulated ROS release was attenuated gradually reaching maximum suppression at 500 nM. Adrenergic receptor (AR) mechanisms using non-AR-selective (labetalol) as well as specific α-(prazosin) and β-(propranolol) receptor antagonists were tested. Results show that only labetalol and propranolol were able to recuperate cytotoxicity in the presence of NE, evidencing a β-receptor-mediated effect. The CB₂ agonist, AM1241, inhibited phagocytosis at 10 µM and spontaneous peroxide release by PMNs. Use of the inverse CB₂ receptor agonist SR144528 led to partial recuperation of ROS production, confirming the functional role of CB₂. Additionally, AM1241 delayed early activation of monocytes and induced suppression of IL-2 and IL-6 levels in response to Candida via lower activity of mammalian target of rapamycin (mTOR). These findings provide new insights into key mechanisms of innate immunity under stressful conditions where ligands to the sympatho-adrenergic and EC system are released.

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The associations between psychological stress and psoriasis: a systematic review

Abstract

Psoriasis is estimated to affect around 2–3% of the general population. More than one-third of Australians report having a significant level of distress in their daily lives. Psychological stress has long been shown to play an important role in the natural history of psoriasis, but the details of this relationship remain to be clearly defined. We performed a systematic review of the literature with the aim of determining whether there is a temporal association between psychological stress as the predictor and onset and/or exacerbation of psoriasis as the outcome measure. Our secondary aim was to establish whether there is a relationship between the degree of psychological stress and clinical severity of psoriasis. Our systematic review demonstrates a probable temporal association between different measures of psychological stress and onset, recurrence, and severity of psoriasis. In the light of this, we suggest clinicians include "stress" as a trigger factor in their psoriasis assessment and consider psychological interventions as adjuncts, particularly in those who identify as "stress-responders".

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Melanocyte abnormalities and senescence in the pathogenesis of idiopathic guttate hypomelanosis

Abstract

Background

Idiopathic guttate hypomelanosis (IGH) is a pigmentary disorder of unknown pathogenesis characterized by small discrete white macules. In the skin, epidermal melanin unit between melanocytes and keratinocytes is responsible for melanin synthesis and equal distribution of melanin pigment.

Objective

Therefore, this study was designed to check the role of melanocytes in the pathogenesis of IGH.

Methods

For this study, six IGH patients and six controls were enrolled. Melanin content was checked in the skin sections and in the cultured melanocytes. Senescence was checked in the lesional skin of IGH patients by comparing the mRNA and protein expression of senescence markers p16, hp1, and p21.

Results

Cultured melanocytes from the IGH patients showed morphological changes in comparison to the control melanocytes. Melanocytes from IGH patients were bigger in size with very small and retracted dendrites as compared to the control melanocytes. Melanin accumulation was more in the IGH patients as compared to the controls. Our results showed that expression of p16, p21, and hp1 was significantly higher in lesional skin of IGH patient as compared to healthy controls.

Conclusion

This study revealed large-sized melanocytes with small and retracted dendrites in IGH patients. Accumulation of more melanin in the IGH melanocytes might be due to problem in the transfer of melanin from melanocytes to keratinocytes. Accumulation of melanin can lead to the senescence in the melanocytes of IGH patients.

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