Chronic UV radiation–induced RORγt+ IL-22–producing lymphoid cells are associated with mutant KC clonal expansion

Chronic ultraviolet (UV) radiation exposure is the greatest risk factor for cutaneous squamous cell carcinoma (cSCC) development, and compromised immunity accelerates this risk. Having previously identified that epidermal Langerhans cells (LC) facilitate the expansion of UV-induced mutant keratinocytes (KC), we sought to more fully elucidate the immune pathways critical to cutaneous carcinogenesis and to identify potential targets of intervention. Herein, we reveal that chronic UV induces and LC enhance a local immune shift toward RORγt+ interleukin (IL)-22/IL-17A–producing cells that occurs in the presence or absence of T cells while identifying a distinct RORγt+ Sca-1+ CD103+ ICOS+ CD2^+/− CCR6+ intracellular CD3+ cutaneous innate lymphoid cell type-3 (ILC3) population (uvILC3) that is associated with UV-induced mutant KC growth. We further show that mutant KC clone size is markedly reduced in the absence of RORγt+ lymphocytes or IL-22, both observed in association with expanding KC clones, and find that topical application of a RORγ/γt inhibitor during chronic UV exposure reduces local expression of IL-22 and IL-17A while markedly limiting mutant p53 KC clonal expansion. We implicate upstream Toll-like receptor signaling in driving this immune response to chronic UV exposure, as MyD88/Trif double-deficient mice also show substantially reduced p53 island number and size. These data elucidate key immune components of chronic UV–induced cutaneous carcinogenesis that might represent targets for skin cancer prevention.

The capacity to identify and therapeutically target the major relevant immune pathways driving disease pathogenesis has proven particularly advantageous for controlling inflammatory cutaneous disorders. This has occurred despite the complexity of lymphoid cell subtypes and cytokine receptor networks active within cutaneous lesions and draining lymph nodes. Marked durable responses are now possible with antibody-based therapeutic agents disrupting, for example, the interleukin (IL)-23/IL-17A (Th17) axis in psoriasis vulgaris (1) and the IL-4/IL-13 (Th2) axis in atopic dermatitis (2).Exposure to ultraviolet (UV) light results in extensive DNA damage to keratinocytes (KC) because of two major phenomena. UV exposure, mostly in the type B UV (UVB) bandwidths, directly targets genomic DNA as a chromophore in which the absorbed energy readily and immediately induces cyclobutane pyrimidine dimers. This is complimented by a more complex indirect (and relatively delayed) series of energy transfers initiated by epidermal molecules, for example, melanin degradation products, that absorb/transfer UV energy before giving rise to triplet state intermediates that may also eventuate into DNA damage (3). Possible fates for such UV-damaged KCs include enzymatic DNA repair, elimination via apoptosis induction, metabolic stress that induces NKG2D-ligand surface expression to mark the damaged cells for elimination, and acquisition of mutations within cell cycle regulators (e.g.TP53, CDKN2A) and stimulators (e.g., RAS, NOTCH-1,2,3) that endow apoptosis resistance and clonal persistence.Martincorena et al. (4) have definitively shown by genomic deep sequencing that such driver mutations persist within chronically sun-exposed skin and that mutant-associated KC clones accumulate as epidermal collections long before the emergence of clinically apparent skin tumors of premalignant actinic keratoses (AK) and cutaneous squamous cell carcinomas (cSCC). Currently, clinical efforts in preventing the outgrowth of these skin neoplasms have included the topical application of chemotherapeutic (e.g., 5-fluorouracil) or immunostimulatory (e.g., imiquimod) agents or the administration of systemic retinoids in attempt to minimize, eliminate, and/or differentiate the mutant clones (5). In this context, we hypothesize that elucidating the immunopathogenesis of chronic UV exposure might identify other potential targets and strategies for skin cancer prevention.It is in this setting of epithelial tissue harboring of persistent driver mutant clones that chronic inflammatory states have long been appreciated for their association with malignant development and progression, for example, inflammatory bowel disease and increased risk of colon cancer (6). Indeed, locally secreted IL-17A and IL-22, both known stimulators of epithelial proliferation, have been implicated in epithelial tumor promotion, including within the gut, lung, and skin (7–9). Nonetheless, IL-22–inhibiting antibodies have met with limited clinical success in preventing or treating intestinal tumors, and while anti–IL-22 antibodies injected into established cSCC might prevent progression (10), the role of IL-22–producing cells in mutant KC clonal expansion and photocarcinogenesis prior to tumor emergence has not been fully elucidated.Recognizing that UVR exposure induces an epidermal damage–driven inflammatory response, we sought to more fully characterize the effects of chronic UV exposure on the local cutaneous immune milieu relevant to the promotion of photocarcinogenesis. A cascade of KC-derived triggers of the local immune response are precipitated by acute UV exposure in the skin, including Toll-like receptor (TLR) ligands (e.g., U1 RNA), antimicrobial peptides (e.g., beta-defensins, S100A7), thymic stromal lymphopoietin (TSLP), and proinflammatory cytokines (e.g., IL-1, IL-36). In addition, chronic UVR has been reported to markedly decrease epidermal Langerhans cells (LC) and increase local and systemic levels of cytokines (e.g., IL-10, TGFβ) that down-regulate cellular antitumor immunity. However, little is known about if and how chronic UV alters the predominant local immune milieu to promote mutant KC clonal expansion so fundamental to cutaneous carcinogenesis. Having previously demonstrated that the absence of epidermal LC markedly decreases mutant KC clone growth during chronic UV exposure, we also considered whether targeting any identifiable associated dominant immune cell population and signals might also limit the expansion of mutant KC and thereby uncouple the tumor-promoting effects of UV-associated inflammation. Herein, we reveal that chronic UV exposure stimulates specific skin immune cell populations, including RORγt-differentiated innate lymphoid cells (ILC) and T cells, that shift the local cytokine milieu to an IL-22/IL-17A–rich state in association with mutant KC growth. Moreover, we identify and implicate a distinct cutaneous (CD4- NKp46- MHCII-) ILC type-3 (ILC3) population (that we term uvILC3) of phenotype RORγt+ Sca-1+ CD103+ ICOS+ CD2^+/− CCR6+ intracellular (ic)CD3+ that drives chronic UV–induced mutant KC clonal expansion in the absence of T cells. We believe that this deciphering of the immunopathogenesis of UV carcinogenesis identifies potential translational targets for cutaneous cancer prevention for patients with chronically photodamaged (mutant clone-harboring) skin and, in particular, potentially for those patients (e.g., organ transplant recipients) with iatrogenically compromised T cell function.     

Overview of Beneficial Effects of (Poly)phenol Metabolites in the Context of Neurodegenerative Diseases on Model Organisms

The rise of neurodegenerative diseases in an aging population is an increasing problem of health, social and economic consequences. Epidemiological and intervention studies have demonstrated that diets rich in (poly)phenols can have potent health benefits on cognitive decline and neurodegenerative diseases. Meanwhile, the role of gut microbiota is ever more evident in modulating the catabolism of (poly)phenols to dozens of low molecular weight (poly)phenol metabolites that have been identified in plasma and urine. These metabolites can reach circulation in higher concentrations than parent (poly)phenols and persist for longer periods of time. However, studies addressing their potential brain effects are still lacking. In this review, we will discuss different model organisms that have been used to study how low molecular weight (poly)phenol metabolites affect neuronal related mechanisms gathering critical insight on their potential to tackle the major hallmarks of neurodegeneration.     

Prevalence and Clinical Features of Celiac Disease in a Cohort of Italian Children with Autism Spectrum Disorders

Background: Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental conditions whose etiopathogenesis derives from a complex interaction between genetic liability and environmental factors. In this framework, mounting evidence suggests that immune system dysfunction could be a risk factor contributing to the development of ASD in at least a subpopulation of individuals. In particular, some studies suggest an association between celiac disease (CD)—a long-term autoimmune disorder that primarily affects the small intestine triggered by the ingestion of gluten—and ASD, while others hypothesized a random link. This investigation aimed to evaluate the prevalence of CD in a large sample of school-aged children with ASD and to characterize their clinical profile. Methods: Medical records of 405 children with ASD aged 5–11 years (mean age: 7.2 years; SD: 1.8 years) consecutively referred to a tertiary-care university hospital between January 2014 and December 2018 were reviewed; among them, 362 had carried out serological testing for CD. Results: Nine patients with positive CD serology were identified, eight of which satisfied the criteria for CD diagnosis. The estimated CD prevalence in ASD children was 2.18% (95% CI, 0.8–3.7), which was not statistically different (1.58%; p = 0.36) from that of an Italian population, matched for age range, considered as a control group (95% CI, 1.26–1.90). Three out of the eight ASD patients with CD did not have any symptoms suggestive of CD. Conclusions: Our findings did not show a higher prevalence of CD in ASD children than in the control population, but could suggest the utility of routine CD screening, given its frequent atypical clinical presentation in this population.     

Nutripedia: The Fight against the Fake News in Nutrition during Pregnancy and Early Life

(1) Background. Early nutrition and lifestyle before and during pregnancy, breastfeeding, infancy, and early childhood can affect the risk of developing common non-communicable diseases during adulthood such as obesity and metabolic syndrome. To support positive long-term outcomes, it is essential to debunk fake news and provide evidence-based nutritional recommendations. “Nutripedia-Informati per Crescere” is a new tool delivering information and education on appropriate nutrition of mothers and babies during pregnancy and the first years of life. (2) Methods. Nutripedia provides the readers with evidence-based scientific contents in an easy-to-access fashion through a website, a social media page and a personalized advice app called “Nutripedia Chatbot”. (3) Results. Forty articles were published on Nutripedia website with more than 220,000 total views. Social channel activation via bloggers reached over 9 million parents. 14,698 users downloaded Nutripedia chatbot, through which a total of 1930 questions were directed to experts while over 24,000 responses were provided by the app. (4) Conclusions. The use of different communication tools delivering evidence-based nutritional information such as Nutripedia is increasing and could offer supportive strategies to provide scientific information to large audiences and contribute fighting fake news. Future research could investigate the effectiveness of this important health campaign.     

A Diamond-Based Dose-per-Pulse X-ray Detector for Radiation Therapy

One of the goals of modern dynamic radiotherapy treatments is to deliver high-dose values in the shortest irradiation time possible. In such a context, fast X-ray detectors and reliable front-end readout electronics for beam diagnostics are crucial to meet the necessary quality assurance requirements of care plans. This work describes a diamond-based detection system able to acquire and process the dose delivered by every single pulse sourced by a linear accelerator (LINAC) generating 6-MV X-ray beams. The proposed system is able to measure the intensity of X-ray pulses in a limited integration period around each pulse, thus reducing the inaccuracy induced by unnecessarily long acquisition times. Detector sensitivity under 6-MV X-photons in the 0.1–10 Gy dose range was measured to be 302.2 nC/Gy at a bias voltage of 10 V. Pulse-by-pulse measurements returned a charge-per-pulse value of 84.68 pC, in excellent agreement with the value estimated (but not directly measured) with a commercial electrometer operating in a continuous integration mode. Significantly, by intrinsically holding the acquired signal, the proposed system enables signal processing even in the millisecond period between two consecutive pulses, thus allowing for effective real-time dose-per-pulse monitoring.     

Tissue viability imaging: mapping skin erythema

Background: Tissue Viability Imaging (TiVi) is an emerging bioengineering technology intended for two-dimensional mapping of skin erythema and blanching. Before TiVi can be effectively used in studies of diseased or damaged skin, the variability in normal skin red blood cell concentration (RBC_conc) requires evaluation.
Objective: To demonstrate how TiVi maps spatial and temporal variations in normal skin RBC_conc at the dorsal side of the hand at rest and during post-occlusive hyperemia.
Methods: Short-term and day-to-day variations in skin RBC_conc were quantified at the dorsal side of the hand in four healthy volunteers at rest. In a separate study, the increase in skin RBC_conc was recorded during post-occlusive hyperemia.
Results: A lower skin RBC_conc (179–184 TiVi units) was observed at the back of the hand and base of the thumb compared with areas adjacent to the nailfoldfold region of the fingers (190–213 TiVi units). The short-term variation (within 70 s) was <2% in all areas of the dorsal side of the hand, while day-to-day variations were in the range 5–7% in the back of the hand and up to 10% in areas adjacent to the nailfold region. In the post-occlusive hyperemia phase, up to a 60% increase in skin RBC_conc was observed in the early part of the reactive hyperemia phase. This increase in skin RBC_conc successively decreased but remained about 18% above the pre-occlusion level after 30 min.
Conclusion: Establishment of healthy skin RBC_conc reference values is important for the design of versatile test procedures for assessment of skin damage caused by vibration tools, chemical exposure or peripheral vascular disease.