To evaluate the efficacy of yellow light-emitting diode (LED) irradiation at 590 nm, alone or in combination with anti-inflammatory active substances against ultraviolet (UV)-induced inflammation in keratinocytes. HaCaT keratinocytes were pretreated with LED yellow light (590 nm) alone or in combination with an antiinflammatory active substance such as glycerophosphoinositol choline (GC), extract of grains of paradise (Aframomum melegueta Schum, AM), or a bisabolol and ginger root extract mixture (Bb-GE) before UVB irradiation. Following each treatment, we measured the levels of inflammatory mediators secreted by keratinocytes. HaCaT keratinocytes treated with UVB (300 mJ cm-²) and then cultured for 24 h exhibited significantly upregulated expression of proinflammatory factors, including interleukin (IL)-1α, prostaglandin E2 (PGE2), and IL-8. After pretreatment with 590 nm LED, UVB-induced inflammatory responses were significantly inhibited. Co-pretreatment with 590 nm LED irradiation and GC further inhibited the expression of IL-1α and IL-8. IL-8 expression was inhibited by co-pretreatment with 590 nm LED irradiation and AM, whereas PGE2 expression was inhibited by co-pretreatment with 590 nm LED irradiation and Bb-GE. Co-treatment with 590 nm LED irradiation and various active substances modulated UVB-induced inflammation in keratinocytes, suggesting the potential application of this approach to prevent damage caused by voluntary sun exposure in daily life.

Bermekimab is a human-derived recombinant monoclonal antibody that exhibits immunoregulatory activity by specifically blocking interleukin-1α activity. Four phase 2 studies evaluated efficacy and safety of bermekimab in patients with moderate-to-severe atopic dermatitis (AD). In addition, a novel human skin explant model was developed to assess bermekimab pharmacokinetics/pharmacodynamics and proteomic/transcriptomic effects. Study 1 (NCT03496974, N = 38) was an open-label, dose escalation study of subcutaneous bermekimab (200 mg or 400 mg). Study 2 (NCT04021862, N = 87) was a double-blind, placebo-controlled, randomized (1:1:1) study of subcutaneous bermekimab (400 mg every week (qw) or every 2 weeks) or placebo. GENESIS (NCT04791319, N = 198) was a double-blind, placebo- and active-comparator-controlled, randomized (1:1:2:2) study of placebo, subcutaneous bermekimab (350 mg or 700 mg qw), or dupilumab. LUNA (NCT04990440, N = 6) was a double-blind, placebo-controlled, randomized (4:1) study of intravenous bermekimab 800 mg qw or placebo. A novel human ex vivo skin pharmacodynamic assay supported phase 0 (NCT03953196) and phase 1 (NCT04544813) studies. In Study 1, 400 mg subcutaneous bermekimab showed improvement in efficacy assessments (e.g., ≥ 75% improvement of EASI over baseline, IGA 0/1, and worst itch); however, efficacy was not confirmed in Study 2 or GENESIS. Consequently, GENESIS and LUNA were terminated early. The novel human ex vivo skin pharmacodynamic assay demonstrated that bermekimab reduced downstream skin injury responses. Although bermekimab showed potential as an AD treatment in preclinical and early open-label trials, larger controlled studies (Study 2 and GENESIS) did not confirm those initial results.

Facial skin redness can be an indicator of skin inflammation, however the physiological connection between facial redness and inflammatory status, as well as its role in age-related skin changes, remains poorly understood. This study aims to investigate the association between the pattern of facial skin redness and biological inflammatory status, as well as age-related changes occurring in the skin. Four studies were conducted recruiting healthy Northern Asian females. Disordered spatial patterns of facial skin redness signals were assessed using image analysis, i.e., the a* gradient algorithm, which quantifies the disordered shape and pattern of localized redness signals on facial skin. This redness pattern was compared with (1) inflammatory protein markers (IL-1Ra/ IL-1α and IL-8) measured from stripped corneocyte samples, (2) gene expression profiles obtained through transcriptome analysis using skin biopsy samples, and (3) the distribution pattern of blood vessel measured using a photoacoustic microscope. The association between the skin redness pattern and current and future ageing-related skin changes was examined through a longitudinal study tracking the same subjects for 10 years. A significant correlation was observed between the a* gradient and the levels of inflammatory cytokines (IL-1Ra/IL-1α and IL-8). Transcriptome analysis revealed upregulation of genes related to acute inflammation, chronic inflammation, cellular senescence, and angiogenesis in subjects with higher a* gradients. The high a* gradient group exhibited an extension of blood vessel diameter and increased blood vessel density, while the medium a* gradient group only exhibited blood vessel extension. Lastly, the 10-year longitudinal study demonstrated that the a* gradient was associated with current and future skin ageing-related attributes, such as increased skin texture and wrinkle formation. The spatial pattern of localized redness on the skin reflects the biological inflammatory status, and this inflammatory condition helps predict current and future age-related skin changes.

Monkeypox virus (MPV) is known to inflict injuries and, in some cases, lead to fatalities in humans. However, the underlying mechanisms responsible for its pathogenicity remain poorly understood. We investigated functions of MPV core proteins, H3L, A35R, A29L, and I1L, and discovered that H3L induced transcriptional perturbations and injuries. We substantiated that H3L upregulated IL1A expression. IL1A, in consequence, caused cellular injuries, and this detrimental effect was mitigated when countered with IL1A blockage. We also observed that H3L significantly perturbed the transcriptions of genes in cardiac system. Mechanistically, H3L occupied the promoters of genes governing cellular injury, leading to alterations in the binding patterns of H3K27me3 and H3K4me3 histone marks, ultimately resulting in expression perturbations. In vivo and in vitro models confirmed that H3L induced transcriptional disturbances and cardiac dysfunction, which were ameliorated when IL1A was blocked or repressed. Our study provides valuable insights into comprehensive understanding of MPV pathogenicity, highlights the significant roles of H3L in inducing injuries, and potentially paves the way for the development of therapeutic strategies targeting IL1A.

BACKGROUND: Lung fibroblasts play a central role in maintaining lung homeostasis and facilitating repair through the synthesis and organization of the extracellular matrix (ECM). This study investigated the cross-talk between interleukin-1 alpha (IL-1α) and transforming growth factor-β (TGF-β) signaling, two key regulators in tissue repair and fibrosis, in the context of lung fibroblast repair in the healthy lung.
RESULTS: Stimulation of lung fibroblasts with TGF-β1 and TGF-β2 induced collagen-I and fibronectin protein expression (p < 0.05), a response inhibited with co-treatment with IL-1α (p < 0.05). Additionally, TGF-β1 and TGF-β2 induced myofibroblast differentiation, and collagen-I gel contraction, which were both suppressed by IL-1α (p < 0.05). In contrast, interleukin (IL)-6, IL-8 and thymic stromal lymphopoietin induced by IL-1α, were unaffected by TGF-β1 or TGF-β2. Mechanistically, IL-1α administration led to the suppression of TGF-β1 and TGF-β2 signaling, through downregulation of mRNA and protein for TGF-β receptor II and the downstream adaptor protein TRAF6, but not through miR-146a that is known to be induced by IL-1α.
CONCLUSIONS: IL-1α acts as a master regulator, modulating TGF-β1 and TGF-β2-induced ECM production, remodeling, and myofibroblast differentiation in human lung fibroblasts, playing a vital role in balancing tissue repair versus fibrosis. Further research is required to understand the dysregulated cross-talk between IL-1α and TGF-β signaling in chronic lung diseases and the exploration of therapeutic opportunities.
METHODS: Primary human lung fibroblasts (PHLF) were treated with media control, or 1 ng/ml IL-1α with or without 50 ng/ml TGF-β1 or TGF-β2 for 1, 6 and 72 h. Cell lysates were assessed for the expression of ECM proteins and signaling molecules by western blot, miRNA by qPCR, mRNA by RNA sequencing and cell supernatants for cytokine production by ELISA. PHLFs were also seeded in non-tethered collagen-I gels to measure contraction, and myofibroblast differentiation using confocal microscopy.

Interleukin-1α is a suggested dual-function cytokine that diverged from interleukin-1β in mammals potentially by acquiring additional biological roles that relate to highly conserved regions in the pro-domain of interleukin-1α, including a nuclear localisation sequence and histone acetyltransferase-binding domains. Why evolution modified pro-interleukin-1α\'s subcellular location and protein interactome, and how this shaped interleukin-1α\'s intracellular role, is unknown. Here we show that TurboID proximity labelling with pro-interleukin-1α suggests a nuclear role for pro-interleukin-1α that involves interaction with histone acetyltransferases, including EP300. We also identify and validate inactivating mutations in the pro-interleukin-1α nuclear localisation sequence of multiple mammalian species, including toothed whales, castorimorpha and marsupials. However, histone acetyltransferase-binding domains are conserved in those species that have lost pro-interleukin-1α nuclear localisation. Together, these data suggest that histone acetyltransferase binding and nuclear localisation occurred together, and that while some species lost the nuclear localisation sequence in their pro-interleukin-1α, histone acetyltransferase binding ability was maintained. The nuclear localisation sequence was lost from several distinct species at different evolutionary times, suggesting convergent evolution, and that the loss of the nuclear localisation sequence confers some important biological outcome.

Acne is a chronic inflammatory skin condition that involves Cutibacterium acnes (C. acnes), which is classified into six main phylotypes (IA1, IA2, IB, IC, II and III). Acne development is associated with loss of C. acnes phylotype diversity, characterised by overgrowth of phylotype IA1 relative to other phylotypes. It was also shown that purified extracellular vesicles (EVs) secreted by C. acnes can induce an acne-like inflammatory response in skin models. We aimed to determine if the inflammatory profile of EVs secreted by C. acnes phylotype IA1 from an inflammatory acne lesion was different from C. acnes phylotype IA1 from normal skin, thus playing a direct role in the severity of inflammation. EVs were produced in vitro after culture of two clinical strains of C. acnes phylotype IA1, T5 from normal human skin and A47 from an inflammatory acne lesion, and then incubated with either human immortalised keratinocytes, HaCaT cells, or skin explants obtained from abdominoplasty. Subsequently, quantitative PCR (qPCR) was performed for human β-defensin 2 (hBD2), cathelicidin (LL-37), interleukin (IL)-1β, IL-6, IL-8, IL-17α and IL-36γ, and ELISA for IL-6, IL-8 and IL-17α. We found that EVs produced in vitro by C. acnes derived from inflammatory acne lesions significantly increased the pro-inflammatory cytokines and anti-microbial peptides at both transcriptional and protein levels compared with EVs derived from normal human skin. We show for the first time that C. acnes EVs from inflammatory acne play a crucial role in acne-associated inflammation in vitro and that C. acnes phylotype IA1 collected from inflammatory acne lesion and normal skin produce different EVs and inflammatory profiles in vitro.

BACKGROUND: Lung ischemia reperfusion injury (IRI) is the principal cause of primary graft dysfunction (PGD) after lung transplantation, affecting short-term and long-term mortality post-transplantation. PANoptosis, a newly identified form of regulated cell death involving apoptosis, necroptosis, and pyroptosis, is now considered a possible cause of organ damage and IRI. However, the specific role of PANoptosis to the development of lung IRI following lung transplantation is still not fully understood.
METHODS: In this study, we identified differentially expressed genes (DEGs) by analyzing the gene expression data from the GEO database related to lung IRI following lung transplantation. PANoptosis-IRI DEGs were determined based on the intersection of PANoptosis-related genes and screened DEGs. Hub genes associated with lung IRI were further screened using Lasso regression and the SVM-RFE algorithm. Additionally, the Cibersort algorithm was employed to assess immune cell infiltration and investigate the interaction between immune cells and hub genes. The upstream miRNAs that may regulate hub genes and compounds that may interact with hub genes were also analyzed. Moreover, an external dataset was utilized to validate the differential expression analysis of hub genes. Finally, the expressions of hub genes were ultimately confirmed using quantitative real-time PCR, western blotting, and immunohistochemistry in both animal models of lung IRI and lung transplant patients.
RESULTS: PANoptosis-related genes, specifically interferon regulatory factor 1 (IRF1) and interleukin 1 alpha (IL1A), have been identified as potential biomarkers for lung IRI following lung transplantation. In mouse models of lung IRI, both the mRNA and protein expression levels of IRF1 and IL1A were significantly elevated in lung tissues of the IRI group compared to the control group. Moreover, lung transplant recipients exhibited significantly higher protein levels of IRF1 and IL1A in PBMCs when compared to healthy controls. Patients who experienced PGD showed elevated levels of IRF1 and IL1A proteins in their blood samples. Furthermore, in patients undergoing lung transplantation, the protein levels of IRF1 and IL1A were notably increased in peripheral blood mononuclear cells (PBMCs) compared to healthy controls. In addition, patients who developed primary graft dysfunction (PGD) exhibited even higher protein levels of IRF1 and IL1A than those without PGD. Furthermore, PANoptosis was observed in the lung tissues of mouse models of lung IRI and in the PBMCs of patients who underwent lung transplantation.
CONCLUSIONS: Our research identified IRF1 and IL1A as biomarkers associated with PANoptosis in lung IRI, suggesting their potential utility as targets for diagnosing and therapeutically intervening in lung IRI and PGD following lung transplantation.

Antiretroviral treatment (ART) has converted HIV from a lethal disease to a chronic condition, yet co-morbidities persist. Incomplete immune recovery and chronic immune activation, especially in the gut mucosa, contribute to these complications. Inflammasomes, multi-protein complexes activated by innate immune receptors, appear to play a role in these inflammatory responses. In particular, preliminary data indicate the involvement of IFI16 and NLRP3 inflammasomes in chronic HIV infection. This study explores inflammasome function in monocytes from people with HIV (PWH); 22 ART-treated with suppressed viremia and 17 untreated PWH were compared to 33 HIV-negative donors. Monocytes were primed with LPS and inflammasomes activated with ATP in vitro. IFI16 and NLRP3 mRNA expression were examined in a subset of donors. IFI16 and NLRP3 expression in unstimulated monocytes correlated negatively with CD4 T cell counts in untreated PWH. For IFI16, there was also a positive correlation with viral load. Monocytes from untreated PWH exhibit increased release of IL-1α, IL-1β, and TNF compared to treated PWH and HIV-negative donors. However, circulating monocytes in PWH are not pre-primed for inflammasome activation in vivo. The findings suggest a link between IFI16, NLRP3, and HIV progression, emphasizing their potential role in comorbidities such as cardiovascular disease. The study provides insights into inflammasome regulation in HIV pathogenesis and its implications for therapeutic interventions.

Intense exercise leads to increased production of free radicals, resulting in an inflammatory response in athletes. For this reason, it was decided to investigate whether a single intensive exercise until exhaustion applied after a 2-week rest period would result in a violation of the pro-oxidant-antioxidant balance. Twenty-seven trained female basketball players (age: 16.55 ± 0.96 years, body mass: 66.40 ± 13.68 kg, height: 173.45 ± 5.14 cm) were enrolled to the study following the application of inclusion and exclusion criteria. Study was conducted at the end of the competitive training phase. Participants underwent incremental treadmill exercise, with blood samples collected before the test, immediately post-exercise, and after a 3-h restitution period. Total antioxidant capacity (TAC) levels increased significantly after exercise and remained unchanged after 3 h. Concentration of interleukin-10 (IL-10) and creatine kinase (CK) significantly increased after exercise and then decreased. Concentration of interleukin-2 (IL-2) was significantly reduced immediately and 3 h after exercise, while interleukin-13 (IL-13), interleukin-1α (IL-1α), and tryptophan (TRP) decreased 3 h after exercise. No significant changes were observed in other biochemical parameters. Obtained results show an increased antioxidant capacity which reduced oxidative stress and inflammation in response to intense exercise indicating that rested athletes have a high adaptation and elevated tolerance to effort.