Staphylococcus aureus proteases trigger eosinophil-mediated skin inflammation.

Staphylococcus aureus skin colonization and eosinophil infiltration are associated with many inflammatory skin disorders, including atopic dermatitis, bullous pemphigoid, Netherton's syndrome, and prurigo nodularis. However, whether there is a relationship between S. aureus and eosinophils and how this interaction influences skin inflammation is largely undefined. We show in a preclinical mouse model that S. aureus epicutaneous exposure induced eosinophil-recruiting chemokines and eosinophil infiltration into the skin. Remarkably, we found that eosinophils had a comparable contribution to the skin inflammation as T cells, in a manner dependent on eosinophil-derived IL-17A and IL-17F production. Importantly, IL-36R signaling induced CCL7-mediated eosinophil recruitment to the inflamed skin. Last, S. aureus proteases induced IL-36α expression in keratinocytes, which promoted infiltration of IL-17-producing eosinophils. Collectively, we uncovered a mechanism for S. aureus proteases to trigger eosinophil-mediated skin inflammation, which has implications in the pathogenesis of inflammatory skin diseases.

Diverse cellular players orchestrate regeneration after wounding.

Fibrosis is one of the largest sources of human morbidity. The skin is a complex organ where interplay between diverse cell types and signalling pathways is essential both in homeostasis and wound repair, which can result in fibrosis or regeneration. This makes skin a useful model to study fibrosis and regeneration. While fibrosis often occurs postinjury, both clinical and laboratory observations suggest skin regeneration, complete with reconstituted cell diversity and de novo hair follicles, is possible. Extensive research performed in pursuit of skin regeneration has elucidated the key players, both cellular and molecular. Interestingly, some cells known for their homeostatic function are not implicated in regeneration or wound-induced hair neogenesis (WIHN), suggesting regeneration harnesses separate functional pathways from embryogenesis or other non-homeostatic mechanisms. For example, classic bulge cells, noted for their role in normally cycling hair follicles, do not finally contribute to long-lived cells in the regenerated tissue. During healing, multiple populations of cells, among them specific epithelial lineages, mesenchymal cells, and immune cells promote regenerative outcomes in the wounded skin. Ultimately, targeting specific populations of cells will be essential in manipulating a postwound environment to favour regeneration in lieu of fibrosis.

Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma.

Congenital hemangioma is a rare vascular tumor that forms in utero. Postnatally, the tumor either involutes quickly (i.e., rapidly involuting congenital hemangioma [RICH]) or partially regresses and stabilizes (i.e., non-involuting congenital hemangioma [NICH]). We hypothesized that congenital hemangiomas arise due to somatic mutation and performed massively parallel mRNA sequencing on affected tissue from eight participants. We identified mutually exclusive, mosaic missense mutations that alter glutamine at amino acid 209 (Glu209) in GNAQ or GNA11 in all tested samples, at variant allele frequencies (VAF) ranging from 3% to 33%. We verified the presence of the mutations in genomic DNA using a combination of molecular inversion probe sequencing (MIP-seq) and digital droplet PCR (ddPCR). The Glu209 GNAQ and GNA11 missense variants we identified are common in uveal melanoma and have been shown to constitutively activate MAPK and/or YAP signaling. When we screened additional archival formalin-fixed paraffin-embedded (FFPE) congenital cutaneous and hepatic hemangiomas, 4/8 had GNAQ or GNA11 Glu209 variants. The same GNAQ or GNA11 mutation is found in both NICH and RICH, so other factors must account for these tumors' different postnatal behaviors.

Positive correlation of hidradenitis suppurativa and ultra-processed foods consumption.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition whose pathogenesis is not well established. An association between HS and obesity is suggested but few studies explore specific dietary drivers. Non-Hispanic Blacks have the highest HS prevalence and obesity rates as well as the highest UPFs consumption rates, as opposed to Hispanics who have the lowest prevalence of HS despite having the second highest obesity rates in the US. Instead, Hispanics have the lowest UPFs consumption and highest minimally processed foods consumption rates in the US. Since HS appears to correlate more with processed food intake than obesity, we explored this connection more carefully. To identify correlations, we cross referenced 3 sources: (1) relative search volume (RSV) on Google Searches for HS. (2) Published data on prevalence of HS and UPFs consumption by nation, state, race, and age. (3) NHANES data on variation of diet patterns in the US. We identified a strong correlation of RSV and UPFs and HS by country (r = 0.83, p < 0.0001) and state in the US (r = 0.82, p < 0.0001) compared to a negative control (melanoma with UPFs; r = 0.35, p = 0.14 by country and r = 0.22, p = 0.23 by state). The variation in searches for HS from 2004 till 2018 (p < 0.0001) was strongly correlated with the increase in UPFs consumption (r = 0.79, p = 0.019) and inversely correlated with the decrease in minimally-processed foods consumption in the US (r = - 0.941, p = 0.0005). These results suggest an association between UPFs consumption and HS, and the need for future studies to address whether limiting UPFs might ameliorate HS.

Glenohumeral Osteoarthritis: A Biological Advantage or a Missed Diagnosis?

(1) Background: Osteoarthritis is a degenerative joint disease that is commonly diagnosed in the aging population. Interestingly, the lower extremity joints have a higher published incidence of osteoarthritis than the upper extremity joints. Although much is known about the disease process, it remains unclear why some joints are more affected than others. (2) Methods: A comprehensive literature review was conducted utilizing the search engines PubMed, Google Scholar, and Elsevier from 2014 to 2024, directing our search to osteoarthritis of various joints, with the focus being on glenohumeral osteoarthritis. (3) Results and Discussion: The literature review revealed a publication difference, which may be explained by the inconsistency in classification systems utilized in the diagnosis of shoulder osteoarthritis. For instance, there are six classification systems employed in the diagnosis of glenohumeral osteoarthritis, making the true incidence and, therefore, the prevalence unobtainable. Furthermore, susceptibility to osteoarthritis in various joints is complicated by factors such as joint anatomy, weight-bearing status, and prior injuries to the joint. (4) Conclusions: This review reveals the lack of understanding of shoulder osteoarthritis's true incidence and prevalence while considering the anatomy and biomechanics of the glenohumeral joint. In addition, this is the first paper to suggest a single criterion for the diagnosis of glenohumeral osteoarthritis.

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs.

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.

Using the Microbiome as a Regenerative Medicine Strategy for Autoimmune Diseases.

Autoimmune (AI) diseases, which present in a multitude of systemic manifestations, have been connected to many underlying factors. These factors include the environment, genetics, individual microbiomes, and diet. An individual's gut microbiota is an integral aspect of human functioning, as it is intimately integrated into the metabolic, mechanical, immunological, and neurologic pathways of the body. The microbiota dynamically changes throughout our lifetimes and is individually unique. While the gut microbiome is ever-adaptive, gut dysbiosis can exert a significant influence on physical and mental health. Gut dysbiosis is a common factor in various AI, and diets with elevated fat and sugar content have been linked to gut microbiome alterations, contributing to increased systemic inflammation. Additionally, multiple AI's have increased levels of certain inflammatory markers such as TNF-a, IL-6, and IL-17 that have been shown to contribute to arthropathy and are also linked to increased levels of gut dysbiosis. While chronic inflammation has been shown to affect many physiologic systems, this review explores the connection between gut microbiota, bone metabolism, and the skeletal and joint destruction associated with various AI, including psoriatic arthritis, systemic lupus erythematosus, irritable bowel disease, and rheumatoid arthritis. This review aims to define the mechanisms of microbiome crosstalk between the cells of bone and cartilage, as well as to investigate the potential bidirectional connections between AI, bony and cartilaginous tissue, and the gut microbiome. By doing this, the review also introduces the concept of altering an individual's specific gut microbiota as a form of regenerative medicine and potential tailored therapy for joint destruction seen in AI. We hope to show multiple, specific ways to target the microbiome through diet changes, rebalancing microbial diversity, or decreasing specific microbes associated with increased gut permeability, leading to reduced systemic inflammation contributing to joint pathology. Additionally, we plan to show that diet alterations can promote beneficial changes in the gut microbiota, supporting the body's own endogenous processes to decrease inflammation and increase healing. This concept of microbial alteration falls under the definition of regenerative medicine and should be included accordingly. By implementing microbial alterations in regenerative medicine, this current study could lend increasing support to the current research on the associations of the gut microbiota, bone metabolism, and AI-related musculoskeletal pathology.

Transepithelial Effect of Probiotics in a Novel Model of Gut Lumen to Nerve Signaling.

Recent studies have shown that the gut microbiome changes brain function, behavior, and psychiatric and neurological disorders. The Gut-Brain Axis (GBA) provides a neuronal pathway to explain this. But exactly how do commensal bacteria signal through the epithelial layer of the large intestine to activate GBA nerve afferents? An in vitro model is described. We differentiated two human cell lines: Caco2Bbe1 into mature epithelium on 0.4-micron filters and then SH-SY5Y into mature neurons in 24-well plates. These were co-cultured by placing the epithelium-laden filters 1 mm above the neurons. Twenty-four hours later they were tri-cultured by apical addition of 107Lactobacillus rhamnosus or Lactobacillus fermentum which settled on the epithelium. Alone, the Caco2bbe1 cells stimulated neurite outgrowth in underlying SH-SY5Y. Beyond this, the lactobacilli were well tolerated and stimulated further neurite outgrowth by 24 h post-treatment, though not passing through the filters. The results provide face validity for a first-of-kind model of transepithelial intestinal lumen-to nerve signaling. The model displays the tight junctional barrier characteristics found in the large intestine while at the same time translating stimulatory signals from the bacteria through epithelial cells to attracted neurons. The model is easy to set-up with components widely available.