Preclinical proof of principle for orally delivered Th17 antagonist miniproteins.

Interleukin (IL)-23 and IL-17 are well-validated therapeutic targets in autoinflammatory diseases. Antibodies targeting IL-23 and IL-17 have shown clinical efficacy but are limited by high costs, safety risks, lack of sustained efficacy, and poor patient convenience as they require parenteral administration. Here, we present designed miniproteins inhibiting IL-23R and IL-17 with antibody-like, low picomolar affinities at a fraction of the molecular size. The minibinders potently block cell signaling in vitro and are extremely stable, enabling oral administration and low-cost manufacturing. The orally administered IL-23R minibinder shows efficacy better than a clinical anti-IL-23 antibody in mouse colitis and has a favorable pharmacokinetics (PK) and biodistribution profile in rats. This work demonstrates that orally administered de novo-designed minibinders can reach a therapeutic target past the gut epithelial barrier. With high potency, gut stability, and straightforward manufacturability, de novo-designed minibinders are a promising modality for oral biologics.

Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.

Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.

Interferon-sensitized hematopoietic progenitors dynamically alter organismal immunity.

Inflammation has enduring impacts on organismal immunity. However, the precise mechanisms by which tissue-restricted inflammation conditions systemic responses are poorly understood. Here, we leveraged a highly compartmentalized model of skin inflammation and identified a surprising type I interferon (IFN)- mediated activation of hematopoietic stem/progenitor cells (HSPCs) that results in profound changes to systemic host responses. Post-inflamed mice were protected from atherosclerosis and had worse outcomes following influenza virus infection. This IFN-mediated HSPC modulation was dependent on IFNAR signaling and could be recapitulated with the administration of recombinant IFNα. Importantly, the transfer of post-inflamed HSPCs was sufficient to transmit the immune suppression phenotype. IFN modulation of HSPCs was rooted both in long-term changes in chromatin accessibility and the emergence of an IFN- responsive functional state from multiple progenitor populations. Collectively, our data reveal the profound and enduring effect of transient inflammation and more specifically type I IFN signaling and set the stage for a more nuanced understanding of HSPC functional modulation by peripheral immune signals.

Inflammatory Memory in Chronic Skin Disease.

Inflammation is a hallmark of remitting-relapsing dermatological diseases. Although a large emphasis has been placed on adaptive immune cells as mediators of relapse, evidence in epithelial and innate immune biology suggests that disease memory is widespread. In this study, we bring to the fore the concept of inflammatory memory or nonspecific training of long-lived cells in the skin, highlighting the epigenetic and other mechanisms that propagate memory at the cellular level. We place these findings in the context of psoriasis, a prototypic flaring disease known to have localized memory, and underscore the importance of targeting memory to limit disease flares.

Staphylococcus scratches its itch.

Itch exacerbates infection and inflammation-associated skin pathology. In this issue of Cell, Deng et al. identify a V8 protease released by Staphylococcus aureus triggering itch via neuronal protease-activated receptor 1. In so doing, they uncover profound consequences of microbial neurosensory modulation and the ensuing scratch-induced tissue damage that potentiates infection.

Cis-regulatory arbitrators of regeneration.

Mammals favor healing with scaring over functional tissue regeneration.1 In this issue of Cell Stem Cell, Mack et al. use "super-healer" mice to identify cis-regulatory variations that direct regenerative versus fibrotic gene expression in wound fibroblasts and they uncover complement factor H as a molecular driver of skin regeneration.2.

Repairing Artifacts in Neural Activity Recordings Using Low-Rank Matrix Estimation.

Electrophysiology recordings are frequently affected by artifacts (e.g., subject motion or eye movements), which reduces the number of available trials and affects the statistical power. When artifacts are unavoidable and data are scarce, signal reconstruction algorithms that allow for the retention of sufficient trials become crucial. Here, we present one such algorithm that makes use of large spatiotemporal correlations in neural signals and solves the low-rank matrix completion problem, to fix artifactual entries. The method uses a gradient descent algorithm in lower dimensions to learn the missing entries and provide faithful reconstruction of signals. We carried out numerical simulations to benchmark the method and estimate optimal hyperparameters for actual EEG data. The fidelity of reconstruction was assessed by detecting event-related potentials (ERP) from a highly artifacted EEG time series from human infants. The proposed method significantly improved the standardized error of the mean in ERP group analysis and a between-trial variability analysis compared to a state-of-the-art interpolation technique. This improvement increased the statistical power and revealed significant effects that would have been deemed insignificant without reconstruction. The method can be applied to any time-continuous neural signal where artifacts are sparse and spread out across epochs and channels, increasing data retention and statistical power.

Event-related variability is modulated by task and development.

In carefully designed experimental paradigms, cognitive scientists interpret the mean event-related potentials (ERP) in terms of cognitive operations. However, the huge signal variability from one trial to the next, questions the representability of such mean events. We explored here whether this variability is an unwanted noise, or an informative part of the neural response. We took advantage of the rapid changes in the visual system during human infancy and analyzed the variability of visual responses to central and lateralized faces in 2-to 6-month-old infants compared to adults using high-density electroencephalography (EEG). We observed that neural trajectories of individual trials always remain very far from ERP components, only moderately bending their direction with a substantial temporal jitter across trials. However, single trial trajectories displayed characteristic patterns of acceleration and deceleration when approaching ERP components, as if they were under the active influence of steering forces causing transient attraction and stabilization. These dynamic events could only partly be accounted for by induced microstate transitions or phase reset phenomena. Importantly, these structured modulations of response variability, both between and within trials, had a rich sequential organization, which in infants, was modulated by the task difficulty and age. Our approaches to characterize Event Related Variability (ERV) expand on classic ERP analyses and provide the first evidence for the functional role of ongoing neural variability in human infants.

Spatial transcriptomics stratifies psoriatic disease severity by emergent cellular ecosystems.

Whereas the cellular and molecular features of human inflammatory skin diseases are well characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high predilection for extracutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active lesion, and clinically uninvolved skin biopsies and integration with public single-cell transcriptomics data revealed marked differences in immune microniches between healthy and inflamed skin. Tissue-scale cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Both lesional and distal nonlesional samples were stratified by skin disease severity and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast-, and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic composition of distal unaffected skin sites. In addition, our study provides a valuable resource for the research community to study spatial gene organization of healthy and inflamed human skin.

Emerging frontiers in regenerative medicine.

Bridging knowledge gaps could enable regenerative therapy.

Taking a Breath: A Systematic Approach to the Development of an Altered Airway eLearning Module by Unit Council Nurses.

After a needs assessment for care of patients with altered airways was performed, gaps in educational materials were identified and hospital learning management system educational resources were created/updated. Frontline nurses and clinical and administrative leaders developed four modules to enhance the care of patients with altered airways. This article describes how professional development specialists could teach nurses how to develop clinical educational modules for specialized populations. [J Contin Educ Nurs. 2023;54(4):153-156.].

Fast and scarless: Prx1+ fibroblasts turbocharge healing.

Our oral cavity has evolved a capacity for rapid healing without scarring. In this issue of JEM, Ko et al. (2022. J. Exp. Med.https://doi.org/10.1084/jem.20221350) identify a Prx1+ fibroblast progenitor that drives oral regeneration by summoning pro-healing TGFß1+ macrophages.

Immune-Epithelial Cross Talk in Regeneration and Repair.

The epithelial tissues that line our body, such as the skin and gut, have remarkable regenerative prowess and continually renew throughout our lifetimes. Owing to their barrier function, these tissues have also evolved sophisticated repair mechanisms to swiftly heal and limit the penetration of harmful agents following injury. Researchers now appreciate that epithelial regeneration and repair are not autonomous processes but rely on a dynamic cross talk with immunity. A wealth of clinical and experimental data point to the functional coupling of reparative and inflammatory responses as two sides of the same coin. Here we bring to the fore the immunological signals that underlie homeostatic epithelial regeneration and restitution following damage. We review our current understanding of how immune cells contribute to distinct phases of repair. When unchecked, immune-mediated repair programs are co-opted to fuel epithelial pathologies such as cancer, psoriasis, and inflammatory bowel diseases. Thus, understanding the reparative functions of immunity may advance therapeutic innovation in regenerative medicine and epithelial inflammatory diseases.

Tracking transitional probabilities and segmenting auditory sequences are dissociable processes in adults and neonates.

Since speech is a continuous stream with no systematic boundaries between words, how do pre-verbal infants manage to discover words? A proposed solution is that they might use the transitional probability between adjacent syllables, which drops at word boundaries. Here, we tested the limits of this mechanism by increasing the size of the word-unit to four syllables, and its automaticity by testing asleep neonates. Using markers of statistical learning in neonates' EEG, compared to adult behavioral performances in the same task, we confirmed that statistical learning is automatic enough to be efficient even in sleeping neonates. We also revealed that: (1) Successfully tracking transition probabilities (TP) in a sequence is not sufficient to segment it. (2) Prosodic cues, as subtle as subliminal pauses, enable to recover words segmenting capacities. (3) Adults' and neonates' capacities to segment streams seem remarkably similar despite the difference of maturation and expertise. Finally, we observed that learning increased the overall similarity of neural responses across infants during exposure to the stream, providing a novel neural marker to monitor learning. Thus, from birth, infants are equipped with adult-like tools, allowing them to extract small coherent word-like units from auditory streams, based on the combination of statistical analyses and auditory parsing cues. RESEARCH HIGHLIGHTS: Successfully tracking transitional probabilities in a sequence is not always sufficient to segment it. Word segmentation solely based on transitional probability is limited to bi- or tri-syllabic elements. Prosodic cues, as subtle as subliminal pauses, enable to recover chunking capacities in sleeping neonates and awake adults for quadriplets.

Langerhans cells are essential components of the angiogenic niche during murine skin repair.

Angiogenesis, the growth of new blood vessels from pre-existing vessels, occurs during development, injury repair, and tumorigenesis to deliver oxygen, immune cells, and nutrients to tissues. Defects in angiogenesis occur in cardiovascular and inflammatory diseases, and chronic, non-healing wounds, yet treatment options are limited. Here, we provide a map of the early angiogenic niche by analyzing single-cell RNA sequencing of mouse skin wound healing. Our data implicate Langerhans cells (LCs), phagocytic, skin-resident immune cells, in driving angiogenesis during skin repair. Using lineage-driven reportersw, three-dimensional (3D) microscopy, and mouse genetics, we show that LCs are situated at the endothelial cell leading edge in mouse skin wounds and are necessary for angiogenesis during repair. These data provide additional future avenues for the control of angiogenesis to treat disease and chronic wounds and extend the function of LCs beyond their canonical role in antigen presentation and T cell immunity.

Intrinsic brain dynamics in the Default Mode Network predict involuntary fluctuations of visual awareness.

Brain activity is intrinsically organised into spatiotemporal patterns, but it is still not clear whether these intrinsic patterns are functional or epiphenomenal. Using a simultaneous fMRI-EEG implementation of a well-known bistable visual task, we showed that the latent transient states in the intrinsic EEG oscillations can predict upcoming involuntarily perceptual transitions. The critical state predicting a dominant perceptual transition was characterised by the phase coupling between the precuneus (PCU), a key node of the Default Mode Network (DMN), and the primary visual cortex (V1). The interaction between the lifetime of this state and the PCU- > V1 Granger-causal effect is correlated with the perceptual fluctuation rate. Our study suggests that the brain's endogenous dynamics are phenomenologically relevant, as they can elicit a diversion between potential visual processing pathways, while external stimuli remain the same. In this sense, the intrinsic DMN dynamics pre-empt the content of consciousness.

Inflammatory memory and tissue adaptation in sickness and in health.

Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege of the immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences-good and bad-of these epigenetic memories and their implications for human health and disease.

Interleukin-17 governs hypoxic adaptation of injured epithelium.

Mammalian cells autonomously activate hypoxia-inducible transcription factors (HIFs) to ensure survival in low-oxygen environments. We report here that injury-induced hypoxia is insufficient to trigger HIF1α in damaged epithelium. Instead, multimodal single-cell and spatial transcriptomics analyses and functional studies reveal that retinoic acid-related orphan receptor γt+ (RORγt+) γδ T cell-derived interleukin-17A (IL-17A) is necessary and sufficient to activate HIF1α. Protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) signaling proximal of IL-17 receptor C (IL-17RC) activates mammalian target of rapamycin (mTOR) and consequently HIF1α. The IL-17A-HIF1α axis drives glycolysis in wound front epithelia. Epithelial-specific loss of IL-17RC, HIF1α, or blockade of glycolysis derails repair. Our findings underscore the coupling of inflammatory, metabolic, and migratory programs to expedite epithelial healing and illuminate the immune cell-derived inputs in cellular adaptation to hypoxic stress during repair.

Epithelial-immune crosstalk in health and disease.

Far from inert structures, our body's epithelial boundaries engage in a dynamic crosstalk with immune cells that is vital for immune surveillance and barrier function. Using the skin and gut epithelium, two structurally distinct but critical environmental interfaces, here we review the context-dependent interactions between myriad immune cells and epithelial subsets. We discuss immune communique reserved for epithelial progenitors and the enduring consequences for tissue fitness. Then, we delve into the cellular and molecular exchanges between differentiated epithelial subsets and adjacent immune cells. Therapeutically targeting stage-specific immune-epithelial interaction could boost regeneration and mitigate inflammatory pathologies.

GRAPPA 2020 Research Award Recipients.

At the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, a summary of the research conducted by the recipients of the 2020 GRAPPA Research Awards was presented by the awardees. The summary of the 4 presentations is provided here.