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Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.

Phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infected Plscr1 -/- mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for the expression of type 3 interferon receptor (Ifn-λr1) upon IAV infection by binding to its promoter. In addition, PLSCR1 interacted with IFN-λR1 on the cell surface of pulmonary epithelial cells following IAV infection, suggesting it also modulated IFN-λ signaling via protein-protein interactions. The lipid scramblase activity of PLSCR1 was found to be dispensable for its anti-flu activity. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1 floxStop ;Foxj1-Cre + mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility to IAV infection, less inflammation, and enhanced Ifn-λr1 expression, suggesting that Plscr1 primarily regulates type 3 IFN signaling as a cell-intrinsic defense factor against IAV in ciliated airway epithelial cells. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

Hermansky-Pudlak syndrome (HPS), particularly types 1 and 4, is characterized by progressive pulmonary fibrosis, a major cause of morbidity and mortality. However, the precise mechanisms driving pulmonary fibrosis in HPS are not fully elucidated. Our previous studies suggested that CHI3L1-driven fibroproliferation may be a notable factor in HPS-associated fibrosis. This study aimed to explore the role of CHI3L1-CRTH2 interaction on type 2 innate lymphoid cells (ILC2s) and explored the potential contribution of ILC2-fibroblast crosstalk in the development of pulmonary fibrosis in HPS. We identified ILC2s in lung tissues from patients with idiopathic pulmonary fibrosis and HPS. Using bleomycin-challenged WT and Hps1-/- mice, we observed that ILC2s were recruited and appeared to contribute to fibrosis development in the Hps1-/- mice, with CRTH2 playing a notable role in ILC2 accumulation. We sorted ILC2s, profiled fibrosis-related genes and mediators, and conducted coculture experiments with primary lung ILC2s and fibroblasts. Our findings suggest that ILC2s may directly stimulate the proliferation and differentiation of primary lung fibroblasts partially through amphiregulin-EGFR-dependent mechanisms. Additionally, specific overexpression of CHI3L1 in the ILC2 population using the IL-7Rcre driver, which was associated with increased fibroproliferation, indicates that ILC2-mediated, CRTH2-dependent mechanisms might contribute to optimal CHI3L1-induced fibroproliferative repair in HPS-associated pulmonary fibrosis.

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

Phospholipid scramblase 1 (PLSCR1) is an interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that influenza A virus (IAV)-infected Plscr1 -/- mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for the expression of type 3 interferon receptor (Ifn-λr1) upon IAV infection by binding to its promoter. In addition, PLSCR1 interacted with IFN-λR1 on the cell surface of pulmonary epithelial cells following IAV infection, suggesting it also modulated IFN-λ signaling via protein-protein interactions. The lipid scramblase activity of PLSCR1 was found to be dispensable for its anti-flu activity. Finally, single-cell RNA sequencing data indicated that Plscr1 expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, Plscr1 floxStop ;Foxj1-Cre + mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility to IAV infection, less inflammation, and enhanced Ifn-λr1 expression, suggesting that Plscr1 primarily regulates type 3 IFN signaling as a cell-intrinsic defense factor against IAV in ciliated airway epithelial cells. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

Phospholipid scramblase 1 (PLSCR1) is an antiviral interferon-stimulated gene (ISG) that has several known anti-influenza functions. However, the mechanisms in relation to its expression compartment and enzymatic activity have not been completely explored. Moreover, only limited animal models have been studied to delineate its role at the tissue level in influenza infections. Our results showed that Plscr1 expression was highly induced by influenza A virus (IAV) infection and in airway epithelial cells treated with IFN-λ. We found that infected mice exhibited exacerbated body weight loss, decreased survival rates, heightened viral replication, and increased lung damage. Interestingly, transcriptomic analyses demonstrated that Plscr1 was required for the expression of type 3 interferon receptor (Ifn-λr1) and a large subset of ISGs upon IAV infection. The impaired expression of Ifn-λr1 and downstream ISGs may be responsible for delayed viral clearance and worse lung inflammation in mice. PLSCR1 acts as a transcriptional activator of by directly binding to its promotor after IAV infection. In addition, PLSCR1 interacted with IFN-λR1 on the cell surface of pulmonary epithelial cells following IAV infection, suggesting it also modulated IFN-λ signaling via protein-protein interactions. The lipid scramblase activity of PLSCR1 was found to be dispensable for its anti-flu activity. Finally, single-cell RNA sequencing data indicated that expression was significantly upregulated in ciliated airway epithelial cells in mice following IAV infection. Consistently, mice with ciliated epithelial cell-specific Plscr1 overexpression showed reduced susceptibility to IAV infection, less inflammation and enhanced Ifn-λr1 expression, suggesting that Plscr1 primarily regulates type 3 IFN signaling as a cell intrinsic defense factor against IAV in ciliated airway epithelial cells. Our research will elucidate virus-host interactions and pave the way for the development of novel anti-influenza drugs that target human elements like PLSCR1, thereby mitigating the emergence of drug-resistant IAV strains.

Background The Symptom Checklist (SCL) developed by the Health Behaviour in School‑aged Children (HBSC) study is widely used to capture the psychosomatic complaints (PSC) of non-clinical children and adolescents. Although its psychometric properties have been well established internationally, the performance of the Mandarin Chinese version remains unclear. This study evaluates the Mandarin Chinese HBSC-SCL’s psychometric properties, develops its norm, and creates the corresponding scoring algorithm. Methods Data were collected from a two-wave cross-sectional survey conducted between June 20 and July 11, 2022, across eight Chinese Human Geography Regions (CHGRs). The sample included 3290 junior secondary school students, obtained through convenience sampling (first wave) and multistage, stratified, cluster sampling (second wave). The surveys were administered anonymously in the school setting, using a paper-and-pencil, self-administered questionnaire. The Mandarin Chinese HBSC-SCL’s unidimensionality was verified using confirmatory factor analysis (CFA), and its psychometric properties were comprehensively evaluated using the partial credit model (PCM) of the Rasch measurement method. Based on the above scientific evidence, the population-based norm and norm-referenced scoring algorithm were developed and created. Results The CFA confirmed that the HBSC-SCL can be considered unidimensional in the Chinese Mainland. Evidence-based on the six features of the Rasch model indicated that the Mandarin Chinese HBSC-SCL has satisfactory psychometric properties. All 5-category rating scales of eight items appropriately differentiated the students’ PSC and demonstrated strong goodness-of-fit. This version also exhibited good unidimensionality and local independence. The Rasch model generated two kinds of reliability indicators, with the item indicators performing well. The person-item map demonstrated acceptable person and item matches, and provided new perspectives for future improvements. Additionally, no substantial uniform differential item functioning (UDIF) was detected across 13 groups (e.g., survey waves, gender, chronological age). Conclusions The Mandarin Chinese HBSC-SCL demonstrates satisfactory psychometric properties and performs well in the Chinese Mainland context. It provides concise self-reported PSC measures for junior secondary school students, potentially applicable to a broader Chinese-speaking population. Its ease of administration, scoring, and interpretation makes it suitable for routine school monitoring, large-scale population surveys, and clinical applications. Additionally, the population-based norm and norm-referenced scoring algorithm support the broader application of this version and offer new insights for interpreting PSC sum scores.