Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in psoriasis: a systematic review and meta-analysis.

Psoriasis is a chronic, inflammatory skin disorder characterized by well-demarcated erythematous lesions with surface scaling. The disease is underpinned by a dysregulated immune response with a shift in the balance of neutrophils, lymphocytes and platelets. We sought to evaluate the novel systemic inflammatory markers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as psoriatic indicators. Pubmed, Web of Science and Scopus were systematically searched for relevant studies. Twenty-four studies consisting of a total of 2,275 psoriatic patients (1,301 males and 974 females) and 2,334 healthy controls (1,401 males and 933 females) were identified for inclusion in the quantitative analysis. The NLR and PLR were found to be significantly increased in psoriatic patients [standardized mean difference (SMD) = 0.68, 95% CI 0.56-0.80, p < 0.01, and SMD = 0.37, 95% CI 0.14-0.60, p < 0.01, respectively]. However, no association between the NLR and PLR with psoriasis severity was detected (p = 0.93, and p = 0.83, respectively). In conclusion, the NLR and PLR are simple and cost-effective markers of psoriatic presence, but their value as severity markers requires further study.

pH and Proton Sensor GPR65 Determine Susceptibility to Atopic Dermatitis.

pH sensing by GPR65 regulates various inflammatory conditions, but its role in skin remains unknown. In this study, we performed a phenome-wide association study and report that the T allele of GPR65-intronic single-nucleotide polymorphism rs8005161, which reduces GPR65 signaling, showed a significant association with atopic dermatitis, in addition to inflammatory bowel diseases and asthma, as previously reported. Consistent with this genetic association in humans, we show that deficiency of GPR65 in mice resulted in markedly exacerbated disease in the MC903 experimental model of atopic dermatitis. Deficiency of GPR65 also increased neutrophil migration in vitro. Moreover, GPR65 deficiency in mice resulted in higher expression of the inflammatory cytokine TNF-α by T cells. In humans, CD4+ T cells from rs8005161 heterozygous individuals expressed higher levels of TNF-α after PMA/ionomycin stimulation, particularly under pH 6 conditions. pH sensing by GPR65 appears to be important for regulating the pathogenesis of atopic dermatitis.

MR1-dependent immune surveillance of the skin contributes to pathogenesis and is a photobiological target of UV light therapy in a mouse model of atopic dermatitis.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are unconventional T cells which recognize microbial metabolites presented by the major histocompatibility complex class I-related molecule MR1. Although MAIT cells have been shown to reside in human and murine skin, their contribution to atopic dermatitis (AD), an inflammatory skin disease associated with barrier dysfunction and microbial translocation, has not yet been determined. METHODS: Genetic deletion of MR1 and topical treatment with inhibitory MR1 ligands, which result in the absence and functional inhibition of MAIT cells, respectively, were used to investigate the role of MR1-dependent immune surveillance in a MC903-driven murine model of AD. RESULTS: The absence or inhibition of MR1 arrested AD disease progression through the blockade of both eosinophil activation and recruitment of IL-4- and IL-13-producing cells. In addition, the therapeutic efficacy of phototherapy against MC903-driven AD could be increased with prior application of folate, which photodegrades into the inhibitory MR1 ligand 6-formylpterin. CONCLUSION: We identified MAIT cells as sentinels and mediators of cutaneous type 2 immunity. Their pathogenic activity can be inhibited by topical application or endogenous generation, via phototherapy, of inhibitory MR1 ligands.

Basophils promote barrier dysfunction and resolution in the atopic skin.

BACKGROUND: The type 2 cytokines IL-4 and IL-13 promote not only atopic dermatitis (AD) but also the resolution of inflammation. How type 2 cytokines participate in the resolution of AD is poorly known. OBJECTIVE: Our aim was to determine the mechanisms and cell types governing skin inflammation, barrier dysfunction, and resolution of inflammation in a model of AD. METHODS: Mice that exhibit expression of IL-4, IL-13, and MCPT8 or that could be depleted of basophils or eosinophils, be deficient in IL-4 or MHC class II molecules, or have basophils lacking macrophage colony-stimulating factor (M-CSF) were treated with calcipotriol (MC903) as an acute model of AD. Kinetics of the disease; keratinocyte differentiation; and leukocyte accumulation, phenotype, function, and cytokine production were measured by transepidermal water loss, histopathology, molecular biology, or unbiased analysis of spectral flow cytometry. RESULTS: In this model of AD, basophils were activated systemically and were the initial and main source of IL-4 in the skin. Basophils and IL-4 promoted epidermal hyperplasia and skin barrier dysfunction by acting on keratinocyte differentiation during inflammation. Basophils, IL-4, and basophil-derived M-CSF inhibited the accumulation of proinflammatory cells in the skin while promoting the expansion and function of proresolution M2-like macrophages and the expression of probarrier genes. Basophils kept their proresolution properties during AD resolution. CONCLUSION: Basophils can display both beneficial and detrimental type 2 functions simultaneously during atopic inflammation.

The Basoph8 Mice Enable an Unbiased Detection and a Conditional Depletion of Basophils.

Basophils are granulocytes involved in parasite immunity and allergic diseases, known for their potent secretion of type 2 cytokines. Identifying their functions has proven to be controversial due to their relative rarity and their complex lineage phenotype. Here, we show that the expression of basophils lineage markers CD200R3 and FcεRIα is highly variable in inflammatory settings and hinders basophils identification by flow cytometry across multiple disease states or tissues. Fluorophore-conjugated antibody staining of these lineage markers strongly activates basophil type 2 cytokine expression, and represents a potential bias for coculture or in vivo transfer experiments. The Basoph8 is a mouse model where basophils specifically express a strong fluorescent reporter and the Cre recombinase. Basophils can be identified and FACS sorted unambiguously by their expression of the enhanced yellow fluorescent protein (eYFP) in these mice. We show that the expression of the eYFP is robust in vivo during inflammation, and in vitro on living basophils for at least 72 h, including during the induction of anaphylactoid degranulation. We bred and characterized the Basoph8xiDTR mice, in which basophils specifically express eYFP and the simian diphtheria toxin receptor (DTR). This model enables basophils conditional depletion relatively specifically ex vivo and in vivo during allergic inflammation and their detection as eYFP+ cells. In conclusion, we report underappreciated benefits of the commercially available Basoph8 mice to study basophils function.

Eosinophils Determine Dermal Thickening and Water Loss in an MC903 Model of Atopic Dermatitis.

Atopic dermatitis (AD) is a highly debilitating disease with significant health impacts worldwide. It has been a difficult disease to treat because of the wide spectrum of clinical manifestations. Therefore, the current clinical management strategies are nonspecific. Previous studies have documented that AD disease progression is precipitated by a combination of skin barrier dysfunction, itch, and immune dysregulation. However, the precise roles played by effector cells and cytokines have not been fully elucidated. To address this, we established a prolonged model of AD, using MC903. The phenotype of this MC903 model closely resembles the one observed in AD patients, including inflammatory parameters, barrier dysfunction, itch, and histopathological characteristics, thereby providing a platform to evaluate targets for the treatment of AD. This model exposed cells and cytokines that are critically associated with disease severity, including eosinophils, TSLP, and IL-4/IL-13. Indeed, eosinophil depletion significantly ameliorated AD pathology, most notably barrier dysfunction, to a similar extent as blocking of the IL-4/IL-13 axis by genetic deletion of STAT6. Thus, this study has identified eosinophils to be critical for the development and maintenance of AD, thereby proposing these effector cells as therapeutic targets for the treatment of AD.