Xiaoning Zeng

In allergic asthma, a detrimental cycle of epithelial barrier destruction, driven predominantly by type 2 inflammation, facilitates allergen exposure to deeper tissues. However, the precise mechanisms underlying this process remain poorly understood. A bioinformatics analysis was performed using public datasets and an independent cohort of asthma patients. Single-cell profiling further elucidated the role of S100 calcium-binding protein P (S100P) in this condition. To investigate the impact of S100P on barrier integrity, human bronchial epithelial cells (16HBE) were stimulated with interleukin-13 (IL-13). The functional interaction between S100P and potential therapeutic compounds was evaluated by molecular docking and dynamics simulation. Our findings revealed significant alterations in the transcriptional regulation of the S100P, with protein levels correlating closely with lung function and eosinophilic inflammation. S100P was predominantly localized in airway epithelial cells (AECs), particularly in the goblet and club cells. It acts as a pivotal signal in maintaining epithelial barrier integrity by regulating tight junction proteins, such as ZO-1 and occludin, and altering transepithelial electrical resistance. Mechanistically, IL-13 markedly upregulated S100P expression in AECs, likely via activation of transcription factor 4 (ATF4). Molecular docking and dynamics simulations demonstrated that S100P interacts with the clinically established antihistamine astemizole and the immunosuppressant celastrol, both of which protect against S100P-induced barrier disruption. Our work identified S100P as a key mediator of airway epithelial barrier dysfunction in asthma, shedding light on the crucial signaling of the IL-13/ATF4/S100P axis. These findings highlight the dual potential of S100P as both a biomarker and a therapeutic target, offering promising strategies for barrier protection in clinical asthma management. The online version contains supplementary material available at 10.1186/s12967-026-08132-y.

Emphysema remains a major challenge in the management of chronic obstructive pulmonary disease (COPD). This study identifies CD207‐positive dendritic cells (CD207 ⁺ DCs) as pivotal mediators of emphysema progression. In patients with COPD, the abundance of CD207 ⁺ DCs in small airways correlates with both emphysema severity and lung function decline (FEV ₁ %pred). In a murine emphysema model, adoptive transfer of CD207 ⁺ DCs reversed the attenuation of emphysema, inflammation and CD8 ⁺ T‐cell expansion in CD207 ‐knockout mice. Mechanistically, cigarette smoke‐induced epithelial GM‐CSF drives the expansion of CD207 ⁺ DCs. Upon activation by damage‐associated molecular patterns (DAMPs), these DCs promote CD8 ⁺ T cell proliferation and activation via Birbeck granule‐mediated MHC‐I antigen cross‐presentation. Collectively, these findings demonstrate that CD207 ⁺ DCs orchestrate a pathogenic CD8 ⁺ T‐cell response in emphysema and represent a promising therapeutic target.

Switching of airway smooth muscle (ASM) cell phenotype from differentiated-contractile to dedifferentiated-proliferative/synthetic state often occurs in asthmatic subjects with airway dysfunction. Evidence has been provided that chloroquine (an agonist of bitter taste receptors) presented benefits to ASM cell function implicated in asthma. However, the underlying mechanism is unclear. House dust mite (HDM)-sensitized mice were administered with chloroquine or dexamethasone before challenge. BALF and lung tissue were obtained for cell counting, histological analysis or ELISA. Primary cultured ASM cells were stimulated with transforming growth factor (TGF)-β1 or H₂O₂. Cells and supernatant were collected for the detection of ASM phenotype, ROS level, and proinflammatory cytokine production. In HDM-sensitized mice, chloroquine attenuated airway hyperresponsiveness (AHR), inflammation and remodeling with an inhibition of immunoglobulin E, IL-4/-13, and TGF-β1 in BALF. ASM cell proliferation (PCNA), hypertrophy (α-SMA), and parasecretion (MMP-9 and MMP-13) were strongly suppressed by chloroquine, hinting the rebalance of the heterogeneous ASM populations in asthmatic airway. Our data in vitro indicated that chloroquine markedly restrained maladaptive alteration in ASM phenotype in concert with a remission of ROS. Using H₂O₂ and PI3K inhibitor (LY294002), we found that the inhibition of oxidative stress level and ROS-AKT signal by chloroquine may serve as a potential mechanism that dedicates to the restoration of the phenotypic imbalance in ASM cells. Overall, the present findings suggested that chloroquine improves asthmatic airway function by controlling ASM cell phenotype shift, sketching a novel profile of chloroquine as a new therapeutic candidate for airway remodeling.

Tuberculosis (TB), is an infectious disease caused by Mycobacterium tuberculosis (M. tuberculosis), and presents with high morbidity and mortality. Alveolar macrophages play an important role in TB pathogenesis although there is heterogeneity and functional plasticity. This study aimed to show the characteristics of alveolar macrophages from bronchioalveolar lavage fluid (BALF) in active TB patients. Single-cell RNA sequencing (scRNA-seq) was performed on BALF cells from three patients with active TB and additional scRNA-seq data from three healthy adults were established as controls. Transcriptional profiles were analyzed and compared by differential geneexpression and functional enrichment analysis. We applied pseudo-temporal trajectory analysis to investigate correlations and heterogeneity within alveolar macrophage subclusters. Alveolar macrophages from active TB patients at the single-cell resolution are described. We found that TB patients have higher cellular percentages in five macrophage subclusters. Alveolar macrophage subclusters with increased percentages were involved in inflammatory signaling pathways as well as the basic macrophage functions. The TB-increased alveolar macrophage subclusters might be derived from M1-like polarization state, before switching to an M2-like polarization state with the development ofM. tuberculosis infection. Cell-cell communications of alveolar macrophages also increased and enhanced in active TB patients. Overall, our study demonstrated the characteristics of alveolar macrophages from BALF in active TB patients by using scRNA-seq.

Among the troika of clinicopathologic features of asthma, airway remodelling has gained sufficient attention for its contribution to progressive airway narrowing. Much effort has been directed at the management of airway smooth muscle cells (ASMCs), but few attempts have proven to prevent the progression of remodelling. Recently, accumulating data have shown the anti-inflammatory/anti-proliferative potency of melatonin (a crucial neurohormone involved in many physiological and pathological processes) in diverse cells. However, no evidence has confirmed its effect on ASMCs. The present study investigates the benefits of melatonin in asthma, with an emphasis on airway remodelling. The results indicated that melatonin significantly attenuated airway hyperresponsiveness (AHR), inflammation and remodelling in a house dust mite (HDM) model. Melatonin markedly alleviated goblet cell hyperplasia/metaplasia, collagen deposition and airway smooth muscle hyperplasia/hypertrophy, implying the achievement of remodelling remission. The data obtained in vitro further revealed that melatonin notably inhibited ASMCs proliferation, VEGF synthesis and cell migration induced by PDGF, which might depend on STAT3 signalling. Moreover, melatonin remarkably relieved ASMCs contraction and reversed ASMCs phenotype switching induced by TGF-β, probably via the Akt/GSK-3β pathway. Altogether, our findings illustrated for the first time that melatonin improves asthmatic airway remodelling by balancing the phenotypic proportions of ASMCs, thus highlighting a novel purpose for melatonin as a potent option for the management of asthma.

To date, aquaporin‑4 (AQP4) has been considered as a critical contributor to neuroinflammation, but little is known about the underlying mechanism. Previous studies have shown that a critical enzyme involved in the sphingomyelin cycle, sphingosine kinase 1 (SPHK1), is implicated in inflammatory processes and contributes to chronic neuroinflammation. The present study investigated the role of AQP4 in proinflammatory cytokine release from astrocytes, with an emphasis on the SPHK1/mitogen‑activated protein kinase (MAPK)/protein kinase B (AKT) pathway. Using primary cultures isolated from AQP4+/+ and AQP4‑/‑ embryos, the production of tumor necrosis factor‑α (TNF‑α)/interleukin‑6 (IL‑6) from astrocytes challenged by lipopolysaccharide (LPS) was compared. The results showed increased secretion of TNF‑α/IL‑6 in the two groups following LPS treatment, but a significantly lower level was observed in the AQP4‑/‑ group compared with that in the AQP4+/+ group. Although upregulation of SPHK1 was detected in the two genotypes, only a mild increase in SPHK1 was found in the AQP4‑/‑ genotype. The phosphorylation of MAPK/AKT was also confirmed to be attenuated in the AQP4‑/‑ group, suggesting decreased MAPK/AKT signaling over time in AQP4‑/‑ astrocytes. Overall, the study findings demonstrated that AQP4 deficiency alleviates proinflammatory cytokine release from astrocytes, in association with the SPHK1/MAPK/AKT pathway. This data improves our understanding of AQP4 in neuroinflammatory events, highlighting a novel profile of SPHK1 as a potential target for the treatment of CNS inflammation.