Byoung-San Moon

Macrophages exhibit considerable functional plasticity in response to environmental cues, contributing to inflammatory initiation, amplification, resolution, tissue remodeling, and tumor progression. Wnt signaling has emerged as an important regulator of these processes, yet its effects vary with the signaling branch, cellular context, and duration of stimulation. This review examines the roles of canonical and typical non‐canonical Wnt signaling in macrophage inflammatory regulation with a focused view on signaling pathways at the intersection of Wnt signaling with nuclear factor‐κB (NF‐κB) in macrophages. Rather than treating these pathways as independent regulators or categorizing their effects as simply pro‐ or anti‐inflammatory, we examine their shared signaling components, subcellular organization, and transcriptional interactions. Particular attention is given to compartment‐specific β‐catenin–NF‐κB crosstalk and the potential role of TCF4 in coordinating gene‐selective inflammatory responses, alongside Wnt5a‐mediated regulatory circuits that link non‐canonical signaling to innate immune competence and inflammatory activity. We further consider the functional significance of these mechanisms across inflammatory responses, tissue remodeling, and tumor‐associated macrophage reprogramming. By integrating molecular mechanisms with macrophage functional plasticity, this review highlights how Wnt signaling may shape distinct inflammatory outcomes according to cellular and disease context. This framework identifies key mechanistic gaps and provides a basis for investigating Wnt‐associated regulatory nodes as potential therapeutic targets while accounting for the need to preserve physiological macrophage functions.

Glioblastoma (GBM) remains one of the most lethal and treatment-refractory brain tumors, characterized by rapid recurrence and profound resistance to conventional therapies. The mechanisms underlying GBM resilience converge on two interdependent axes: intratumoral heterogeneity and adaptive tumor microenvironment (TME) remodeling, which engage in reciprocal crosstalk to promote immune evasion, invasion, and tumor persistence. Epigenetic regulation has emerged as a central determinant of tumor plasticity and cellular adaptability within this context. Methyl-CpG-binding domain protein 3 (MBD3), a core structural and regulatory component of the NuRD complex, represents a functionally distinctive epigenetic regulator that operates beyond canonical methylation-dependent pathways. With well-established roles in lineage commitment and neural development, MBD3 has been increasingly implicated in GBM progression, glioma stem cell maintenance, and therapeutic resistance. In parallel, GBM actively co-opts non-neoplastic TME components - including microglia, the resident innate immune sentinels of the central nervous system - which exert context-dependent tumor-supportive and tumor-suppressive functions. Understanding how MBD3 shapes tumor–immune interactions and modulates innate immune regulation is therefore of growing biological and translational importance. This review provides an overview of the MBD protein family and delineates the multifaceted roles of MBD3 in developmental and GBM biology, with particular emphasis on tumor-intrinsic heterogeneity and TME remodeling. By integrating epigenetic, cellular, and immunological perspectives, we highlight emerging evidence linking MBD3 to tumor plasticity and immune modulation, and propose hypothetical regulatory frameworks that warrant experimental investigation. Clarifying the context-dependent functions of MBD3 may yield mechanistic insights into GBM pathogenesis and inform the development of novel epigenetic therapeutic strategies.

Introduction: Neurological complications are increasingly recognized as a significant consequence of COVID-19; however, time-resolved, brain-specific characterization of transcriptional alterations underlying SARS-CoV-2–associated neuroinflammation and neuronal injury remain limited. We hypothesized that brain transcriptional responses evolve dynamically during acute SARS-CoV-2 infection, resulting in temporal transcriptional programs. Methods: KRT18-hACE2 transgenic mice were intranasally inoculated with SARS-CoV-2. Brain was harvested at 4 and 6 days post-infection (dpi) for analyses. Results: Immunohistochemical analyses confirmed a broad spectrum of viral neurotropism and gliotropism, accompanied by an increased apoptotic burden, particularly in cortical neurons (ClCas3/SATB2+). Robust activation of myeloid cells (Iba1+/CD68+) provided evidence of neuroinflammation. Cytokine/chemokine profiling demonstrated pronounced upregulation of inflammatory mediators (CXCL10, IL-12p40, CCL12), alongside reduced CX3CL1, suggesting impaired neuron–microglia communication. Whole-transcriptome and gene ontology analyses uncovered stage-dependent molecular programs, with early alterations at 4 dpi enriched in protein ubiquitination, vesicle trafficking, and synaptic processes, followed by intensified innate immune activation and engagement of chromosomal maintenance pathways at 6 dpi. In parallel, pronounced suppression of mitochondrial function at 6 dpi, pointing to energy exhaustion and transcriptional-translational discordance, as supported by digital PCR and a substantial reduction in COXIV protein levels. Discussion: These findings provide a time-resolved molecular landscape of SARS-CoV-2–induced neuroinflammation and metabolic stress, highlighting CNS vulnerability during severe infection and suggesting pathways potentially relevant to COVID-19-associated sequelae.

The resurgence of neurotropic viruses capable of breaching the central nervous system (CNS) has intensified the demand for advanced in vitro models to clarify the mechanisms underlying cellular tropism, neuropathogenesis, and host–virus interactions. Brain organoids (BOs), derived from human pluripotent stem cells, have emerged as physiologically relevant platforms that simulate key features of CNS architecture, cellular diversity, and functional neural circuitry. These three-dimensional systems offer a compelling model for decoding the intricate virus–host interplay within a brain-like microenvironment. This review provides a succinct overview of conventional models employed in neurotropic virus research and summarizes recent innovations in BO technologies. In a novel conceptual pivot, we introduce a functional classification of BO applications based on distinct scientific objectives within neurovirology. Anchoring current findings within this framework provides a more integrative and practical lens through which the evolving utility of BOs can be assessed. Ultimately, we highlight the transformative potential of BOs in accelerating the development of precision therapeutics for CNS infections.

Acquisition of neural progenitor cell (NPC) homeostasis through balancing self-renewal and differentiation is essential for brain development and function. Among the mechanisms controlling these processes, canonical Wnt signaling and the Mbd3–NuRD complex, with prominent suppressive effects on neurogenesis, have been described as crucial parts of the core regulatory circuit. Here we explored Mbd3 as a downstream element of the canonical Wnt signalosomes. Specifically, dynamic modulation of Wnt signaling through activator (Wnt3a) and inhibitor (DKK1) resulted in parallel alterations in β-catenin and Mbd3 expression patterns. Also, overexpression and depletion of GSK3β respectively promoted and attenuated Mbd3 ubiquitination, highlighting that the canonical Wnt cascade promotes Mbd3 stability. Downstream of the Wnt–β-catenin pathway, Mbd3 represses transcription of neurogenesis-associated genes by triggering NuRD complex assembly, thereby promoting NPC stemness. This new Wnt–Mbd3 axis extends the current understanding of the canonical Wnt network in directing neuronal cell-fate determination in NPCs, suggesting this pathway as a potential target for driving neural stem cell reprogramming and neuronal lineage commitment.