Biology subjects

Jania, C. M.

Publications and source records attributed to Jania, C. M..

2 recordsLinked to original sources

bioRxiv2026

Transmural Single-Nucleus Transcriptomics Nominates Candidate Disease Programs in Human Necrotizing Enterocolitis

Background & Aims: Necrotizing enterocolitis (NEC) is a life-threatening disease of premature infants marked by inflammation, ischemia, mucosal injury, and, in advanced cases, necrosis extending into deeper layers of the intestinal wall. Because NEC affects specialized, interacting cells in a developing intestine, we used single-nucleus transcriptomics to build a transmural, cell-type-resolved map and nominate hypothesis-generating disease programs distinct from maturation. Methods: Full-thickness intestinal specimens from fetal/prenatal controls, acute NEC cases, and infant controls were analyzed by single-nucleus RNA sequencing (snRNA-seq). Fetal and infant samples served as developmental references. Analyses included cell annotation, NEC-versus-infant differential expression, gene ontology (GO), cross-lineage recurrence, cell death signatures, and developmental maturity. Results: We profiled 53,735 nuclei by snRNA-seq and resolved 34 epithelial, stromal, vascular, immune, neuronal, glial, and smooth muscle populations. We used a morphology-based nuclei scoring system for sample selection that predicted high-quality transcript recovery. NEC nuclei were represented across this cellular landscape, with recurrent gene-expression changes suggesting shared inflammatory recruitment, antimicrobial/redox defense, stress adaptation, complement/vascular activation, reduced homeostatic signaling, and cell death-associated regulation. Developmental maturity analysis identified fetal-like expression levels in subsets of NEC-regulated genes. Proliferative crypt populations retained DNA repair/cell-cycle programs with inflammatory, hypoxic, and ER-stress features, while absorptive enterocytes showed reduced digestive, transport, detoxification, and terminal villus-function programs. Secretory-lineage changes implicated goblet mucus-barrier responses with reduced glycosylation, trafficking, and hydration; enteroendocrine changes in epithelial defense, metabolic stress, and neural signaling; and Paneth cell retention of antimicrobial effector transcripts despite altered ER quality control, autophagy, and granule delivery in NEC. Non-epithelial programs implicated stromal Wnt/BMP niche loss, impaired lymphatic drainage/scavenging, macrophage cytokine activation with reduced clearance machinery, neuroglial circuit defects, and altered smooth muscle contraction-relaxation balance. Conclusions: This single nuclear intestinal cell atlas nominates multicellular programs that may govern NEC initiation, progression toward tissue destruction, and resolution toward functional recovery.

pathology↗

bioRxiv2025

T cell AIM2 Exacerbates Lung Inflammation in OVA-LPS and HDM-induced Asthma Models

Asthma is a complex airway inflammatory disease characterized by immune dysregulation, with diverse cellular contributors to inflammation that result in airway hyperresponsiveness (AHR) and excessive immune responses. The role of the inflammasome in asthma is conflicted. AIM2 is an innate immune receptor that activates the inflammasome through DNA binding. The clinical relevance of AIM2 in asthma is supported by analysis of blood or endobronchial biopsies from patients with severe asthma, showing increased AIM2 but not NLRP3 expression. We investigated the role of AIM2 in allergic asthma using ovalbumin (OVA)-LPS and house dust mite (HDM)- induced models. AIM2 expression was elevated in lung homogenates and bronchoalveolar lavage fluid (BALF) cells from allergen-induced groups compared to controls. In the OVA-LPS model, deletion of Aim2 led to reduced airway smooth muscle actin expression and DNA damage, contributing to decreased AHR and lung inflammation in whole body Aim2-/- mice. Surprisingly, cell-specific deletion in CD4+ T cells but not regulatory T cells or myeloid cells significantly affected AHR, indicating AIM2 in CD4+ T cells is a main driver of pathogenesis. Additionally, in HDM-induced asthma, Aim2-/- mice also exhibited reduced AHR. Cell-specific deletion reveals that AIM2 in CD4+ T cells promotes AHR and cytokine production, while AIM2 in myeloid cells modulates IgG1 levels and IL-13-producing CD4+ T cells, and the percentage of alveolar macrophages in BALF. These findings reveal that AIM2 differentially regulates HDM-induced allergic asthma through distinct exacerbating roles in T cells and myeloid cells, highlighting its potential as a therapeutic target. SignificanceAllergic asthma is a complex, heterogeneous disease characterized by airway inflammation and hyper-responsiveness. AIM2, an inflammasome activated by DNA, has emerged as a critical regulator of inflammatory diseases. In humans, AIM2 expression is elevated in severe asthma. In vivo studies highlight AIM2 as a key modulator of allergic asthma in both OVA-LPS and HDM- induced models. Surprisingly, its functional relevance in both models is mediated by its intrinsic role in T cells, while a modest role in myeloid cells is restricted to the HDM model. AIM2 promotes airway hyper-responsiveness and lung inflammation through enhancing type II cytokines, immune subpopulations and DNA damage response. These findings suggest AIM2 as a biomarker and therapeutic target for managing asthma, particularly in severe asthma subtypes.

immunology↗