Bone loss due to an increased osteoclast activity is common in osteoporosis and rheumatoid arthritis. For the first time, we observed an inhibition of osteoclast formation and bone resorption by outer-membrane vesicles (OMVs) from a Gram-negative, pathogenic bacterium, Proteus mirabilis (P.M). Gene ontogeny and KEGG enrichment analyses of miRNA and mRNA sequencing data demonstrated a significant effect of P.M OMVs on mitochondrial functions and apoptotic pathways. OMVs induced mitochondrial dysfunction through an increased level of intracellular ROS, collapse of mitochondrial membrane potential (ΔΨm), and modulation of Bax, Bcl-2, caspase-3, and cytochrome c expression. In addition, P.M OMVs strongly inhibited miR-96-5p expression, which caused an upregulation of ATP binding cassette subfamily A member 1 (Abca1) in osteoclasts leading to an increased level of mitochondria-dependent apoptosis. Moreover, treatment with P.M but not Escherichia coli OMVs attenuated bone loss in experimental osteoporosis and collagen-induced arthritis. Collectively, we demonstrated osteoprotective functions of OMVs from Proteus mirabilis, which downregulated miR-96-5p causing an increased Abca1 expression and mitochondria-dependent apoptosis.
Sex-bias is more obvious in several autoimmune disorders, but not in psoriasis. However, estrogen levels fluctuate during puberty, menstrual cycle, pregnancy, and menopause, which are related to variations in psoriasis symptoms observed in female patients. Estrogen has disease promoting or ameliorating functions based on the type of immune responses and tissues involved. To investigate the effects of estrogen on psoriasis, at first, we developed an innate immunity dependent mannan-induced psoriasis model, which showed a clear female preponderance in disease severity in several mouse strains. Next, we investigated the effects of endogenous and exogenous estrogen using ovariectomy and sham operated mice. 17-β-estradiol (E2) alone promoted the skin inflammation and it also significantly enhanced mannan-induced skin inflammation. We also observed a prominent estrogen receptor-β (ER-β) expression in the skin samples, especially on keratinocytes. Subsequently, we confirmed the effects of E2 on psoriasis using ER-β antagonist (PHTPP) and agonist (DPN). In addition, estrogen was found to affect the expression of certain genes (vgll3 and cebpb), microRNAs (miR146a and miR21), and immune cells (DCs and γδ T cells) as well as chemokines (CCL5 and CXCL10) and cytokines (TNF-α, IL-6, IL-22, IL-23, and IL-17 family), which promoted the skin inflammation. Thus, we demonstrate a pathogenic role for 17-β-estradiol in promoting skin inflammation, which should be considered while designing new treatment strategies for psoriasis patients.
Psoriasis is a genetically determined, environmentally triggered, immune system-mediated autoimmune disease. Different animal models are needed to investigate the complex pathological mechanisms underlying this disease. Therefore, we established mannan induced psoriasis model and compared with the most commonly used imiquimod induced psoriasis in terms of disease, induction of innate immune cells, expression of cytokines and the effect of dexamethasone treatment. Mannan significantly induced more severe psoriasis with better disease relapsing feature than IMQ. As determined by immunohistochemistry, IMQ induced significantly more infiltration of CD11c + and F4/80 + cells than mannan in the skin. However, cytometric analysis showed a significant increase in the percentage of Gr-1 + neutrophils in the spleen and lymph nodes as well as F4/80 + macrophages in the spleen after mannan exposure. Variation in the percentage of significantly increased Vγ4 T cells was also found to be dependent on the lymphoid organs tested. However, there is a clear difference between these models in terms of expression of certain cytokine genes: IL-22, IL-23, IL-17E and IL-17F were expressed more predominantly in mannan induced inflammation, while IL-6 and IL-17A expressions were significantly higher in IMQ model. Interestingly, dexamethasone treatment strongly reduced epidermal thickness and histological scores induced by mannan than IMQ. Despite inducing psoriasis-like inflammation, certain differences and similarities were observed in the immune responses induced by mannan and IMQ. However, mannan induced psoriasis model is relatively more simple, economical and less harmful to mice with an increased possibility to develop a chronic psoriasis model by exposing mice to mannan.
Psoriasis vulgaris is a chronic, recurring, multisystem inflammatory disease, commonly presenting with welldemarcated red plaques with silvery scaling that can occur on any part of the skin, including the nails, palms, soles, and genitalia, with the most commonly seen areas being elbows, knees, and scalp. 1 Psoriasis vulgaris is a non-communicable disease, plaque areas can have severe pruritus, which result in pinpoint bleeding (Auspitz's sign) upon scratching. 2 The precise causes of psoriasis remain unknown but it is believed to be related to immune-regulation with genetic and environmental contributions. 1,3 People with psoriasis experience physical discomfort, and the visual appearance of plaques can cause embarrassment as well, both of them significantly impact quality of life (QoL). 4 Conventional therapies for psoriasis target immune response, reducing inflammation and keratinocyte proliferation. The German evidence-and consensus-based (S3) guideline for the treatment of psoriasis states that there is no clear treatment protocol as cases must be evaluated on an individual basis. 5 The key recommendations for basic therapy involve one or a combination of topical and phototherapy/systemic therapy. 5 For moderate-tosevere cases, the use of biologics, such as TNF-α inhibitor, IL-17 antibody, and IL-12/IL-23 antagonists, has become a welcome addition in psoriasis management. 1 The National Institute for Health and Care Excellence (NICE) recommends topical therapy on top of emollients as the first line treatment for psoriasis vulgaris. 6 Clinical guidelines also mentioned the limitations of corticosteroids, including causing psoriasis to become unstable, causing irreversible skin atrophy, or systemic side effects upon long-term or extensive use. Subsequently, they advised against longterm use of corticosteroid by suggesting a break after 4 weeks and replacement with non-steroid-based topical This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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