Lupus dermal fibroblasts are proinflammatory and exhibit a profibrotic phenotype in scarring skin disease.

Fibroblasts are stromal cells known to regulate local immune responses important for wound healing and scar formation; however, the cellular mechanisms driving damage and scarring in patients with cutaneous lupus erythematosus (CLE) remain poorly understood. Dermal fibroblasts in patients with systemic lupus erythematosus (SLE) experience increased cytokine signaling in vivo, but the effect of inflammatory mediators on fibroblast responses in nonscarring versus scarring CLE subtypes is unclear. Here, we examined responses to cytokines in dermal fibroblasts from nonlesional skin of 22 patients with SLE and CLE and 34 individuals acting as healthy controls. Notably, inflammatory cytokine responses were exaggerated in SLE fibroblasts compared with those from individuals acting as healthy controls. In lesional CLE biopsies, these same inflammatory profiles were reflected in single-cell RNA-Seq of SFRP2+ and inflammatory fibroblast subsets, and TGF-ß was identified as a critical upstream regulator for inflammatory fibroblasts in scarring discoid lupus lesions. In vitro cytokine stimulation of nonlesional fibroblasts from patients who scar from CLE identified an upregulation of collagens, particularly in response to TGF-ß, whereas inflammatory pathways were more prominent in nonscarring patients. Our study revealed that SLE fibroblasts are poised to hyperrespond to inflammation, with differential responses among patients with scarring versus nonscarring disease, providing a potential skin-specific target for mitigating damage.

Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity.

Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. Here, we show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV)B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is significantly upregulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. Strikingly, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cGAS-STING activation compared to B-DNA. ZBP1 knockdown abrogates UV-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.

Pansclerotic morphea is characterized by IFN-γ responses priming dendritic cell fibroblast crosstalk to promote fibrosis.

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-ß response. In vitro, TGF-ß and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

Mobile Acceptance and Commitment Therapy With Distressed First-Generation College Students: Microrandomized Trial.

BACKGROUND: Extant gaps in mental health services are intensified among first-generation college students. Improving access to empirically based interventions is critical, and mobile health (mHealth) interventions are growing in support. Acceptance and commitment therapy (ACT) is an empirically supported intervention that has been applied to college students, via mobile app, and in brief intervals. OBJECTIVE: This study evaluated the safety, feasibility, and effectiveness of an ACT-based mHealth intervention using a microrandomized trial (MRT) design. METHODS: Participants (N=34) were 18- to 19-year-old first-generation college students reporting distress, who participated in a 6-week intervention period of twice-daily assessments and randomization to intervention. Participants logged symptoms, moods, and behaviors on the mobile app Lorevimo. After the assessment, participants were randomized to an ACT-based intervention or no intervention. Analyses examined proximal change after randomization using a weighted and centered least squares approach. Outcomes included values-based and avoidance behavior, as well as depressive symptoms and perceived stress. RESULTS: The findings indicated the intervention was safe and feasible. The intervention increased values-based behavior but did not decrease avoidance behavior. The intervention reduced depressive symptoms but not perceived stress. CONCLUSIONS: An MRT of an mHealth ACT-based intervention among distressed first-generation college students suggests that a larger MRT is warranted. Future investigations may tailor interventions to contexts where intervention is most impactful. TRIAL REGISTRATION: ClinicalTrials.gov NCT04081662; https://clinicaltrials.gov/show/NCT04081662. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/17086.

Mobile Acceptance and Commitment Therapy in Bipolar Disorder: Microrandomized Trial.

BACKGROUND: Mobile interventions promise to fill in gaps in care with their broad reach and flexible delivery. OBJECTIVE: Our goal was to investigate delivery of a mobile version of acceptance and commitment therapy (ACT) for individuals with bipolar disorder (BP). METHODS: Individuals with BP (n=30) participated in a 6-week microrandomized trial. Twice daily, participants logged symptoms in the app and were repeatedly randomized (or not) to receive an ACT intervention. Self-reported behavior and mood were measured as the energy devoted to moving toward valued domains or away from difficult emotions and with depressive d and manic m scores from the digital survey of mood in BP survey (digiBP). RESULTS: Participants completed an average of 66% of in-app assessments. Interventions did not significantly impact the average toward energy or away energy but did significantly increase the average manic score m (P=.008) and depressive score d (P=.02). This was driven by increased fidgeting and irritability and interventions focused on increasing awareness of internal experiences. CONCLUSIONS: The findings of the study do not support a larger study on the mobile ACT in BP but have significant implications for future studies seeking mobile therapy for individuals with BP. TRIAL REGISTRATION: ClinicalTrials.gov NCT04098497; https://clinicaltrials.gov/ct2/show/NCT04098497.

Regulation of Photosensitivity by the Hippo Pathway in Lupus Skin.

OBJECTIVE: Photosensitivity is one of the most common manifestations of systemic lupus erythematosus (SLE), yet its pathogenesis is not well understood. The normal-appearing epidermis of patients with SLE exhibits increased ultraviolet B (UVB)-driven cell death that persists in cell culture. Here, we investigated the role of epigenetic modification and Hippo signaling in enhanced UVB-induced apoptosis seen in SLE keratinocytes. METHODS: We analyzed DNA methylation in cultured keratinocytes from SLE patients compared to keratinocytes from healthy controls (n = 6/group). Protein expression was validated in cultured keratinocytes using immunoblotting and immunofluorescence. An immortalized keratinocyte line overexpressing WWC1 was generated via lentiviral vector. WWC1-driven changes were inhibited using a large tumor suppressor kinase 1/2 (LATS1/2) inhibitor (TRULI) and small interfering RNA (siRNA). The interaction between the Yes-associated protein (YAP) and the transcriptional enhancer associate domain (TEAD) was inhibited by overexpression of an N/TERT cell line expressing a tetracycline-inducible green fluorescent protein-tagged protein that inhibits YAP-TEAD binding (TEADi). Apoptosis was assessed using cleaved caspase 3/7 and TUNEL staining. RESULTS: Hippo signaling was the top differentially methylated pathway in SLE versus control keratinocytes. SLE keratinocytes (n = 6) showed significant hypomethylation (Δß = -0.153) and thus overexpression of the Hippo regulator WWC1 (P = 0.002). WWC1 overexpression increased LATS1/2 kinase activation, leading to YAP cytoplasmic retention and altered proapoptotic transcription in SLE keratinocytes. Accordingly, UVB-mediated apoptosis in keratinocytes could be enhanced by WWC1 overexpression or YAP-TEAD inhibition, mimicking SLE keratinocytes. Importantly, inhibition of LATS1/2 with either the chemical inhibitor TRULI or siRNA effectively eliminated enhanced UVB-apoptosis in SLE keratinocytes. CONCLUSION: Our work unravels a novel driver of photosensitivity in SLE: overactive Hippo signaling in SLE keratinocytes restricts YAP transcriptional activity, leading to shifts that promote UVB apoptosis.

A Mixed-Methods Analysis of Mobile ACT Responses From Two Cohorts.

Background: Mobile transdiagnostic therapies offer a solution to the challenges of limited access to psychological care. However, it is unclear if individuals can actively synthesize and adopt concepts and skills via an app without clinician support. Aims: The present study measured comprehension of and engagement with a mobile acceptance and commitment therapy (ACT) intervention in two independent cohorts. Authors hypothesized that participants would recognize that behaviors can be flexible in form and function and respond in an ACT process-aligned manner. Methods: Mixed-methods analyses were performed on open-ended responses collected from initial participants (n = 49) in two parallel micro-randomized trials with: 1) first-generation college students (FGCSs) (n = 25) from a four-year public research university and 2) individuals diagnosed with bipolar disorder (BP) (n = 24). Twice each day over six weeks, participants responded to questions about mood and behavior, after which they had a 50-50 chance of receiving an ACT-based intervention. Participants identified current behavior and categorized behavior as values-based or avoidant. Interventions were selected randomly from 84 possible prompts, each targeting one ACT process: engagement with values, openness to internal experiences, or self-awareness. Participants were randomly assigned to either exploratory (10 FGCS, 9 BP) or confirmatory (15 FGCS, 15 BP) groups for analyses. Responses from the exploratory group were used to inductively derive a qualitative coding system. This system was used to code responses in the confirmatory group. Coded confirmatory data were used for final analyses. Results: Over 50% of participants in both cohorts submitted a non-blank response 100% of the time. For over 50% of participants, intervention responses aligned with the target ACT process for at least 96% of the time (FGCS) and 91% of the time (BP), and current behavior was labeled as values-based 70% (FGCS) and 85% (BP) of the time. Participants labeled similar behaviors flexibly as either values-based or avoidant in different contexts. Dominant themes were needs-based behaviors, interpersonal and family relationships, education, and time as a cost. Conclusions: Both cohorts were engaged with the app, as demonstrated by responses that aligned with ACT processes. This suggests that participants had some level of understanding that behavior can be flexible in form and function.

Digital solutions for shaping mood and behavior among individuals with mood disorders.

Mood disorders present on-going challenges to the medical field, with difficulties ranging from establishing effective treatments to understanding complexities of one's mood. One solution is the use of mobile apps and wearables for measuring physiological symptoms and real-time mood in order to shape mood and behavior. Current digital research is focused on increasing engagement in monitoring mood, uncovering mood dynamics, predicting mood, and providing digital microinterventions. This review discusses the importance and risks of user engagement, as well as barriers to improving it. Research on mood dynamics highlights the possibility to reveal data-driven computational phenotypes that could guide treatment. Mobile apps are being used to track voice patterns, GPS, and phone usage for predicting mood and treatment response. Future directions include utilizing mobile apps to deliver and evaluate microinterventions. To continue these advances, standardized reporting and study designs should be considered to improve digital solutions for mood disorders.

Optimizing an Acceptance and Commitment Therapy Microintervention Via a Mobile App With Two Cohorts: Protocol for Micro-Randomized Trials.

BACKGROUND: Given gaps in the treatment of mental health, brief adaptive interventions have become a public health imperative. Transdiagnostic interventions may be particularly appropriate given high rates of medical comorbidity and the broader reach of transdiagnostic therapies. One such approach utilized herein is acceptance and commitment therapy (ACT), which is focused on increasing engagement with values, awareness, and openness to internal experiences. ACT theory posits that experiential avoidance is at the center of human suffering, regardless of diagnosis, and, as such, seeks to reduce unworkable experiential avoidance. OBJECTIVE: Our objective is to provide the rationale and protocol for examining the safety, feasibility, and effectiveness of optimizing an ACT-based intervention via a mobile app among two disparate samples, which differ in sociodemographic characteristics and symptom profiles. METHODS: Twice each day, participants are prompted via a mobile app to complete assessments of mood and activity and are then randomly assigned to an ACT-based intervention or not. These interventions are questions regarding engagement with values, awareness, and openness to internal experiences. Participant responses are recorded. Analyses will examine completion of assessments, change in symptoms from baseline assessment, and proximal change in mood and activity. A primary outcome of interest is proximal change in activity (eg, form and function of behavior and energy consumed by avoidance and values-based behavior) following interventions as a function of time, symptoms, and behavior, where we hypothesize that participants will focus more energy on values-based behaviors. Analyses will be conducted using a weighted and centered least squares approach. Two samples will run concurrently to assess the capacity of optimizing mobile ACT in populations that differ widely in their clinical presentation and sociodemographic characteristics: individuals with bipolar disorder (n=30) and distressed first-generation college students (n=50). RESULTS: Recruitment began on September 10, 2019, for the bipolar sample and on October 5, 2019, for the college sample. Participation in the study began on October 18, 2019. CONCLUSIONS: This study examines an ACT-based intervention among two disparate samples. Should ACT demonstrate feasibility and preliminary effectiveness in each sample, a large randomized controlled trial applying ACT across diagnoses and demographics would be indicated. The public health implications of such an approach may be far-reaching. TRIAL REGISTRATION: ClinicalTrials.gov NCT04098497; https://clinicaltrials.gov/ct2/show/NCT04098497; ClinicalTrials.gov NCT04081662; https://clinicaltrials.gov/ct2/show/NCT04081662. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/17086.