Experimental and Molecular Medicine最新文献

The brain is a highly complex, multicellular organ composed of diverse neuronal and nonneuronal cell types that function in concert to maintain central nervous system homeostasis. Among the glial populations, astrocytes are critical regulators of neuronal function. Under physiological conditions, astrocytes provide essential metabolic support, modulate neurotransmitter release and maintain neuronal health. Traditionally viewed as passive and supporting cells, astrocytes are now recognized as dynamic and responsive elements within the central nervous system. In response to pathological insults, astrocytes undergo significant changes in function, morphology and gene expression-a process known as reactive astrogliosis. Reactive astrocytes acquire heterogeneous characteristics that can contribute to brain disorders via the non-cell-autonomous mechanisms. However, the drivers of this transformation-and their shift from neuronal guardians to potential contributors to pathology-remain incompletely understood. Here we explore the complex, multidimensional roles of astrocytes and how reactive states alter their primary functions. We focus on the dual protective and pathological roles of astrocytes, particularly the transition from healthy to heterogeneous reactive forms, with the aim of understanding their overall impact on the progression of neurodegenerative diseases.

Interferon regulatory factor 5 (IRF5) is a key regulator of inflammatory responses; however, its role in chronic obstructive pulmonary disease remains unknown. A previous study showed increased IRF5 expression in the lungs of cigarette smoke (CS)-induced emphysema. Here we investigated the function of IRF5 in emphysema using Irf5-knockout (KO) mice. Alveolar destruction, inflammatory cell infiltration, cytokine levels and pyroptosis-related gene expression were assessed in CS-induced emphysema. To investigate the role of immune cells, Ly6C⁺⁺ (Ly6C^high) monocytes and Ly6C^high T cells from Irf5-KO mice were introduced into emphysema mice. The correlation between IRF5 levels and emphysema in humans was also evaluated. Irf5-KO mice showed decreased alveolar destruction after CS exposure. NLRP3 expression was suppressed, and gasdermin D cleavage was altered in Irf5-KO mice, suggesting a protective effect against pyroptotic cell death. Moreover, Ly6C^high monocytes and Ly6C^high T cells were more abundant in the lungs of Irf5-KO mice after CS exposure, and their transfer attenuated NLRP3 expression and alveolar damage. Furthermore, IRF5 expression was significantly elevated in lung tissues from patients. Our findings highlight IRF5 as a critical regulator of emphysema pathogenesis via NLRP3-mediated pyroptosis and Ly6C^high-expressing immune cells. Targeting IRF5 may be a potential therapeutic strategy for chronic obstructive pulmonary disease.

Mucopolysaccharidosis (MPS) type IIIB is the progressive degeneration of the central nervous system. Resveratrol is proposed as a potential therapeutic molecule as a drug reducing inflammation and for improving behavior of MPS mice. Here we investigated autophagy in correlation with immune response in an MPS IIIB mouse model. The effects of resveratrol on mouse behavior and the levels of selected cytokines that influence the inflammation were assessed. The study was performed on both male and female mice treated or not with resveratrol. The results of behavioral, molecular and biochemical experiments confirmed that autophagy and immune response are disturbed in MPS IIIB mice. A correlation between behavioral disturbances and levels of heparan sulfate and TLR4 could be observed. The FOXO3 transcription factor was identified as one of the key factors in the resveratrol-mediated stimulation of the autophagy process in the MPS IIIB mouse model, though it was not the sole pathway induced by this compound. We conclude that resveratrol can modulate the degradation of glycosaminoglycans and also may contribute to the reduction of inflammation and the normalization of animal behavior in the MPS IIIB model.

Immune cells rely on surface immunoreceptors to sense their environment. While the downstream signaling pathways of many immunoreceptors are well characterized, the initial molecular events that trigger signaling upon ligand engagement remain incompletely understood. Here, in this Review, we outline our current understanding of this immunoreceptor signal initiation problem, using the T cell antigen receptor (TCR) as a prototype. We synthesize decades of research on the TCR's unique functional requirements and explore how these properties constrain potential triggering mechanisms. We evaluate prominent models of TCR signal initiation and highlight their respective strengths, limitations, complementary aspects and areas of ongoing debate. A central focus is the role of mechanical force in TCR triggering and antigen recognition for which we consider evidence for TCR-pMHC catch bonds, the capacity of T cells to generate endogenous forces and how these might modulate receptor-ligand kinetics and conformational changes to enhance antigen discrimination beyond classical kinetic proofreading models. By comparing TCR triggering with that of other immunoreceptors such as B cell receptors and Fc receptors, we discuss both shared principles and receptor-specific differences. This Review aims to consolidate current knowledge, reconcile conflicting findings and identify critical unanswered questions, in hopes of charting a path toward understanding how immunoreceptors convert ligand binding into cellular responses.