Increasing evidence for the pathogenic role of keratinocytes in lupus
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Loss of TC-PTP in keratinocytes leads to increased UVB-induced autophagy
Ultraviolet B (UVB) radiation can distort cellular homeostasis and predispose the skin to carcinogenesis. Amongst the deteriorating effects of the sun’s UVB radiation on cellular homeostasis is the formation of DNA photoproducts. These photoproducts can cause significant changes in the structure and conformation of DNA, inducing gene mutations which may accumulate to trigger the formation of skin cancer. Photoproducts are typically repaired by nucleotide excision repair. Notwithstanding, when the repair mechanism fails, apoptosis ensues to prevent the accumulation of mutations and to restore cellular homeostasis. This present study reports that T-cell protein tyrosine phosphatase (TC-PTP) can increase UVB-induced apoptosis by inhibiting autophagy-mediated cell survival of damaged keratinocytes. TC-PTP deficiency in 3PC mouse keratinocytes led to the formation of autophagic vacuoles and increased expression of LC3-II. We established human TC-PTP-deficient (TC-PTP/KO) HaCaT cells using the CRISPR/Cas9 system. TC-PTP/KO HaCaT cells exhibited increased cell survival upon UVB exposure, which was accompanied by increased expression of LC3-II and decreased expression of p62 compared to control cells. Pretreatment of TC-PTP/KO HaCaT cells with early-phase autophagy inhibitor, 3-methyladenine significantly decreased the expression of LC3-II and reduced cell survival in response to UVB irradiation in comparison with untreated TC-PTP/KO cells. Pretreatment of TC-PTP/KO HaCaT cells with late-phase inhibitor, chloroquine also significantly reduced cell viability with increased accumulation of LC3-II after UVB irradiation compared to untreated counterpart cells. While UVB significantly increased apoptosis in the engineered (Mock) cells, this was not observed in similarly treated TC-PTP/KO HaCaT cells. However, chloroquine treatment increased apoptosis in TC-PTP/KO HaCaT cells. Examination of human squamous cell carcinomas (SCCs) revealed that TC-PTP expression was inversely correlated with LC3 expression. Our findings suggest that TC-PTP negatively regulates autophagy-mediated survival of damaged cells following UVB exposure, which can contribute to remove damaged keratinocytes via apoptosis.
The AhR-Ovol1-Id1 regulatory axis in keratinocytes promotes epidermal and immune homeostasis in atopic dermatitis-like skin inflammation
The skin is our outer permeability and immune defense barrier against myriad external assaults. Aryl hydrocarbon receptor (AhR) senses environmental factors and regulates barrier robustness and immune homeostasis. AhR agonists have been approved by the FDA for psoriasis treatment and are in clinical trials for the treatment of atopic dermatitis (AD), but the underlying mechanism of action remains poorly defined. Here, we report that OVOL1/Ovol1 is a conserved and direct transcriptional target of AhR in epidermal keratinocytes. We show that OVOL1/Ovol1 influences AhR-mediated regulation of keratinocyte gene expression and that OVOL1/Ovol1 ablation in keratinocytes impairs the barrier-promoting function of AhR, exacerbating AD-like inflammation. Mechanistically, we have identified Ovol1’s direct downstream targets genome-wide and provided in vivo evidence supporting the role of Id1 as a functional target in barrier maintenance, disease suppression, and neutrophil accumulation. Furthermore, our findings reveal that an IL-1/dermal γδT cell axis exacerbates type 2 and 3 immune responses downstream of barrier perturbation in Ovol1-deficient AD skin. Finally, we present data suggesting the clinical relevance of OVOL1 and ID1 functions in human AD skin. Our study highlights a keratinocyte-intrinsic AhR-Ovol1-Id1 regulatory axis that promotes both epidermal and immune homeostasis in the context of skin inflammation, identifying new therapeutic targets.
Syk inhibitor attenuates lupus in FcγRIIb−/− mice through the Inhibition of DNA extracellular traps from macrophages and neutrophils via p38MAPK-dependent pathway
Spleen tyrosine kinase (Syk), an important hub of immune signaling, is activated by several signalings in active lupus which could be interfered by Syk inhibitor but is still not completely evaluated in innate immune cells associated with lupus activity. Hence, a Syk inhibitor (fostamatinib; R788) was tested in vivo using Fc gamma receptor-deficient (FcγRIIb−/−) lupus mice and in vitro (macrophages and neutrophils). After 4 weeks of oral Syk inhibitor, 40 week-old FcγRIIb−/− mice (a full-blown lupus model) demonstrated less prominent lupus parameters (serum anti-dsDNA, proteinuria, and glomerulonephritis), systemic inflammation, as evaluated by serum TNFa, IL-6, and citrullinated histone H3 (CitH3), gut permeability defect, as indicated by serum FITC dextran assay, serum lipopolysaccharide (LPS), and serum (1 → 3)-β-D-glucan (BG), extracellular traps (ETs) and immune complex deposition in spleens and kidneys (immunofluorescent staining of CitH3 and immunoglobulin G) than FcγRIIb−/− mice with placebo. Due to the spontaneous elevation of LPS and BG in serum, LPS plus BG (LPS + BG) was used to activate macrophages and neutrophils. After LPS + BG stimulation, FcγRIIb−/− macrophages and neutrophils demonstrated predominant abundance of phosphorylated Syk (Western blotting), and the pro-inflammatory responses (CD86 flow cytometry analysis, supernatant cytokines, ETs immunofluorescent, and flow cytometry-based apoptosis). With RNA sequencing analysis and western blotting, the Syk-p38MAPK-dependent pathway was suggested as downregulating several inflammatory pathways in LPS + BG-activated FcγRIIb−/− macrophages and neutrophils. Although both inhibitors against Syk and p38MAPK attenuated macrophage and neutrophil inflammatory responses against LPS + WGP, the apoptosis inhibition by p38MAPK inhibitor was not observed. These results suggested that Syk inhibitor (fostamatinib) improved the severity of lupus caused by FcγRIIb defect partly through Syk-p38MAPK anti-inflammation that inhibited both ET formation and cytokine production from innate immune cells.
Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity
Rare variants in melanocortin 4 receptor gene (MC4R) result in a severe form of early-onset obesity; however, it is unclear how these variants may affect abdominal fat distribution, intrahepatic fat accumulation, and related metabolic sequelae.
Genotype of PAX2-related disorders correlates with kidney and ocular manifestations
PAX2-related disorders encompass renal coloboma syndrome (RCS) and hereditary focal segmental glomerulosclerosis (FSGS) type 7. We retrospectively analyzed 27 Korean patients with PAX2 pathogenic variants detected between 2004 and 2022 and conducted a literature review of 328 cases, including 301 previously reported. In our cohort, 19 had RCS, 4 had FSGS, and 4 had isolated congenital anomalies of the kidneys and urinary tract. Patients were classified by variant type into predicted loss of function (pLoF) and non-pLoF variant groups, and by variant location into paired domain and other sites group. pLoF variants were predominantly associated with RCS, observed in 82% of patients in both our data (18 of 22, P = 0.017) and the literature (140 of 171, P < 0.001). Kidney failure developed in 52% of Korean patients at a median age of 14.5 years, with no difference in kidney survival between variant types. However, the literature review indicated faster progression to kidney failure in patients with pLoF variants (11.0 vs. 24.0 years; pLoF, n = 138 vs. non-pLoF, n = 71; P = 0.002), with no significant difference by variant location. Ocular manifestations were more common, had earlier onset, and were more severe in the pLoF variants group in our cohort (P = 0.038). The literature confirmed a higher prevalence of ocular involvement in patients with pLoF variants (pLoF, n = 175 vs. non-pLoF, n = 88; P < 0.001) and in those with paired domain variants (P = 0.01). pLoF variants in PAX2 were associated with worse kidney and ocular outcomes. These findings support genotype-phenotype correlations, contributing to tailored management in patients with PAX2-related disorders.
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