Skin microbiome dysbiosis in leprosy cases

<p>The human skin possesses a microenvironment conducive to the growth of the skin microbiome, which plays in many physiological functions in cutaneous immunity homeostasis and maturation. The microbiome composition depends on many variables, such as endogenous (host condition) or exogenous (environmental) factors and topographic location. Host-skin microbes’ interaction can be mutualism or pathogenicity. Dysbiosis or alteration in skin microbiota is associated with various dermatological diseases, including leprosy. Dysbiosis is driven by the alteration of the microbial communities themselves or due to the intrinsic features of the host. Leprosy is a chronic granulomatous disease caused by <em>Mycobacterium leprae</em> targeting the nerves and skin, leading to loss of sensation on the skin, with or without dermatologic lesions, and correlated with long term consequences, such as deformities or disability. Microvascular dysfunction and significant alterations in capillary structure due to invasion of <em>M. leprae</em> lead to altered hydration levels of the skin caused by disruption of blood flow; which changes the resident microbial community structure. The skin microbiome composition differences in leprosy patient’s skin lesions were observed; skin microbial diversity in the leprosy patients was lower than in healthy individuals. The diversity reduction was observed in freshly diagnosis leprosy patients, those at various stages of MDT, and post-MDT; indicated that both the interaction between skin microbial community and<strong> </strong><em>M. leprae</em> or the ongoing therapeutic regimen impacted the skin microbiome variation. </p><p> </p>

Cellular Senescence and Inflammaging in the Skin Microenvironment

Cellular senescence and aging result in a reduced ability to manage persistent types of inflammation. Thus, the chronic low-level inflammation associated with aging phenotype is called “inflammaging”. Inflammaging is not only related with age-associated chronic systemic diseases such as cardiovascular disease and diabetes, but also skin aging. As the largest organ of the body, skin is continuously exposed to external stressors such as UV radiation, air particulate matter, and human microbiome. In this review article, we present mechanisms for accumulation of senescence cells in different compartments of the skin based on cell types, and their association with skin resident immune cells to describe changes in cutaneous immunity during the aging process.

Developmental cell programs are co-opted in inflammatory skin disease

The skin confers biophysical and immunological protection through a complex cellular network established early in embryonic development. We profiled the transcriptomes of more than 500,000 single cells from developing human fetal skin, healthy adult skin, and adult skin with atopic dermatitis and psoriasis. We leveraged these datasets to compare cell states across development, homeostasis, and disease. Our analysis revealed an enrichment of innate immune cells in skin during the first trimester and clonal expansion of disease-associated lymphocytes in atopic dermatitis and psoriasis. We uncovered and validated in situ a reemergence of prenatal vascular endothelial cell and macrophage cellular programs in atopic dermatitis and psoriasis lesional skin. These data illustrate the dynamism of cutaneous immunity and provide opportunities for targeting pathological developmental programs in inflammatory skin diseases.

Shedding light on the role of keratinocyte-derived extracellular vesicles on skin-homing cells

Extracellular vesicles (EVs) are secretory lipid membranes with the ability to regulate cellular functions by exchanging biological components between different cells. Resident skin cells such as keratinocytes, fibroblasts, melanocytes, and inflammatory cells can secrete different types of EVs depending on their biological state. These vesicles can influence the physiological properties and pathological processes of skin, such as pigmentation, cutaneous immunity, and wound healing. Since keratinocytes constitute the majority of skin cells, secreted EVs from these cells may alter the pathophysiological behavior of other skin cells. This paper reviews the contents of keratinocyte-derived EVs and their impact on fibroblasts, melanocytes, and immune cells to provide an insight for better understanding of the pathophysiological mechanisms of skin disorders and their use in related therapeutic approaches.

Monocyte-derived Prostaglandin E2 inhibits antigen-specific cutaneous immunity during ageing

Ageing results in a decline in immune function. We showed previously that healthy older humans (>65 years old) have reduced antigen-specific cutaneous immunity to varicella zoster virus (VZV) antigen challenge. This was associated with p38 MAP kinase driven inflammation that was induced by mild tissue injury caused by the injection of the antigen itself. Here we show that non-specific injury induced by injection of air or saline into the skin of older adults recruits CCR2+CD14+ monocytes by CCL2 produced by senescent fibroblasts. These monocytes reduced TRM proliferation via secretion of prostaglandin E2 (PGE2). Pre-treatment with a p38-MAPK inhibitor (Losmapimod) in older adults in vivo significantly decreased CCL2 expression, recruitment of monocyte into the skin, COX2 expression and PGE2 production. This enhanced the VZV response in the skin. Therefore, local inflammation arising from interaction between senescent cells and monocytes leads to immune decline in the skin during ageing, a process that can be reversed.SummaryInflammation resulting from tissue injury blocks antigen-specific cutaneous immunity during ageing. Monocytes recruited to the skin inhibit TRM function through COX2-derived prostaglandin E2 production. Blocking inflammation and resulting prostaglandin E2 production with a p38-MAP kinase inhibitor significantly enhances cutaneous antigen-specific responses.

Controlling the Growth of the Skin Commensal Staphylococcus epidermidis Using D-Alanine Auxotrophy

ABSTRACTUsing live microbes as therapeutic candidates is a strategy that has gained traction across multiple therapeutic areas. In the skin, commensal microorganisms play a crucial role in maintaining skin barrier function, homeostasis, and cutaneous immunity. Alterations of the homeostatic skin microbiome are associated with a number of skin diseases. Here, we present the design of an engineered commensal organism, Staphylococcus epidermidis, for use as a live biotherapeutic product (LBP) candidate for skin diseases. The development of novel bacterial strains whose growth can be controlled without the use of antibiotics, or genetic elements conferring antibiotic resistance, enables modulation of therapeutic exposure and improves safety. We therefore constructed an auxotrophic strain of S. epidermidis that requires exogenously supplied D-alanine. The S. epidermidis strain, NRRL B-4268 Δalr1Δalr2Δdat (SEΔΔΔ) contains deletions of three biosynthetic genes: two alanine racemase genes, alr1 and alr2 (SE1674 and SE1079), and the D-alanine aminotransferase gene, dat (SE1423). These three deletions restricted growth in D-alanine deficient media, pooled human blood, and skin. In the presence of D-alanine, SEΔΔΔ colonized and increased expression of human β-defensin 2 in cultured human skin models in vitro. SEΔΔΔ, showed a low propensity to revert to D-alanine prototrophy, and did not form biofilms on plastic in vitro. These studies support the potential safety and utility of SEΔΔΔ as a live biotherapeutic strain whose growth can be controlled by D-alanine.