Social deficits represent a core symptom domain of autism spectrum disorder (ASD), which is often comorbid with sleep disturbances. In this issue of the JCI, Sun et al. explored a medial septum (MS) circuit linking these behaviors in a neuroligin 3 conditional knockout model of autism. They identified GABAergic neuron hyperactivity following neuroligin 3 deletion in the MS. This hyperactivity resulted in the inhibition of the downstream preoptic area (POA) and hippocampal CA2 region, resulting in sleep loss and social memory deficits, respectively. Inactivating the hyperactive MS GABA neurons or activating the POA or CA2 rescued the behavioral deficits. Together, these findings deepen our understanding of neural circuits underlying social and sleep deficits in ASD.
Claire E. Cho, Dahee Jung, Reesha R. Patel
Ineffective recovery from pneumonia can lead to interstitial lung disease characterized by aberrant epithelial cells in fibrotic regions. In this issue of the JCI, Lin et al. define molecular pathways leading to the development and persistence of keratin 5+ (Krt5+) epithelial cells in the alveolar parenchyma when mice struggle to recover from influenza infection. The receptor for IFN-γ on lung epithelium was essential for the formation of aberrant Krt5+ cells and fibrotic lung disease. The transcription factor Yes-associated protein 1 (YAP) was necessary for persistence of these Krt5+ cells, and IFN-γ activated YAP in lung epithelial cells via JAK, focal adhesion kinase (FAK), and Src kinases. These findings establish a targetable pathway underlying some of the pulmonary postacute sequelae of pneumonia.
Bradley E. Hiller, Joseph P. Mizgerd
Obesity is a growing public health concern that affects the longevity and lifestyle of all human populations including children and older individuals. Diverse factors drive obesity, making it challenging to understand and treat. While recent studies highlight the importance of GPCR signaling for metabolism and fat accumulation, we lack a molecular description of how obesogenic signals accumulate and propagate in cells, tissues, and organs. In this issue of the JCI, Jiang et al. utilized germline mutagenesis to generate a missense variant of GRP75, encoded by the Thinner allele, which resulted in mice with a lean phenotype. GPR75 accumulated in the cilia of hypothalamic neurons. However, mice with the Thinner allele showed defective ciliary localization with resistance to fat accumulation. Additionally, GPR75 regulation of fat accumulation appeared independent of leptin and ADCY3 signaling. These findings shed light on the role of GPR75 in fat accumulation and highlight the need to identify relevant ligands.
Marcelo Chávez, Anushweta Asthana, Peter K. Jackson
Fibrosis is a common manifestation of most progressive and degenerative diseases, with myofibroblast activation and matrix accumulation playing a key role. In this issue of the JCI, Hoeft et al. identify the important role of ADAMTS12 in fibroblast activation. ADAMTS12, a secreted protein, is involved in extracellular matrix (ECM) remodeling, cell signaling, and inflammation. ADAMTS12 facilitates proteolysis by cleaving various substrates such as ECM components, which are vital for cellular signaling and remodeling. Additionally, it modulates cell-matrix interactions, influencing cell adhesion and migration, and plays an important role in the inflammatory processes. Understanding the role of ADAMTS12 offers potential therapeutic insights for targeting fibrosis in progressive diseases.
Bernhard Dumoulin, Katalin Susztak
Microbial mimicry, the process in which a microbial antigen elicits an immune response and breaks tolerance to a structurally related self-antigen, has long been proposed as a mechanism in autoimmunity. In this issue of the JCI, Dolton et al. extend this paradigm by demonstrating that a naturally processed peptide from Klebsiella oxytoca acts as a superagonist for autoreactive T cells in type 1 diabetes (T1D). Reframing microbial mimics as superagonists that are thousands of times better at binding disease-associated autoreactive T cell receptors than self-peptides serves to narrow the search space for relevant sequences in the vast microbial proteome. Moreover, the identified superagonists have implications for the intervention and personalized monitoring of T1D that may carry over to other autoimmune diseases with microbial mimicry.
Jesusa Capera, Michael L. Dustin
Epigallocatechin gallate (EGCG) is a polyphenol plant metabolite abundant in tea that has demonstrated antifibrotic properties in the lung. In this issue of the JCI, Cohen, Brumwell, and colleagues interrogated the mechanistic action of EGCG by investigating lung biopsies of patients with mild interstitial lung disease (ILD) who had undergone EGCG treatment. EGCG targeted the WNT inhibitor SFRP2, which was enriched in fibrotic fibroblasts and acted as a TGF-β target, with paracrine effects leading to pathologic basal metaplasia of alveolar epithelial type 2 cells. This study emphasizes the epithelial-mesenchymal trophic unit as a central signaling hub in lung fibrosis. Understanding and simultaneous targeting of interlinked signaling pathways, such as TGF-β and WNT, paves the road for future treatment options for pulmonary fibrosis.
Olivier Burgy, Melanie Königshoff
Intestinal fibrosis is a severe complication of Crohn’s disease, often requiring surgical intervention. Despite extensive research efforts, an effective treatment to prevent or reverse intestinal fibrosis remains elusive. In this issue of the JCI, Zhang, Wang, and colleagues employed single-cell RNA sequencing to uncover mechanisms of the fibrotic process. They identified a key fibroblast subset of TWIST1+FAP+ cells that interacts with CXCL9+ macrophages. TWIST1 emerged as a central regulator of the fibrotic microenvironment, representing a promising therapeutic target for effectively treating intestinal fibrosis.
Giovanni Santacroce, Antonio Di Sabatino
Many aspects of breast cancer metastasis remain poorly understood, despite its clinical importance. In this issue of the JCI, Winkler et al. have applied an elegant patient-derived xenograft (PDX) model to map the transcriptomes of single cells in matched primary tumors and lung metastases across 13 breast cancer PDX models. They identified distinct transcriptional changes associated with metastatic evolution in lowly and highly metastatic primary tumors. Furthermore, by classifying the “epithelial-mesenchymal plasticity” (EMP) state of single cells, they revealed that considerable EMP heterogeneity exists among primary and metastatic human breast cancer cells. However, the EMP profile of a tumor does not change substantially upon metastasis. These findings give an unprecedentedly detailed view into the transcriptional heterogeneity and evolution of metastatic human breast cancer.
Melissa Q. Reeves
Obesity is a known driver of endometrial cancer. In this issue of the JCI, Gómez-Banoy and colleagues investigated a cohort of patients with advanced endometrial cancer treated with immune checkpoint inhibitors targeting the interaction between programmed cell death receptor-1 (PD-1) and its ligand (PD-L1). Notably, a BMI in the overweight or obese range was paradoxically associated with improved progression-free and overall survival. A second paradox emerged from CT analyses of visceral adipose tissue, viewed as an unhealthy fat depot in most other contexts, the quantity of which was also associated with improved treatment outcomes. Though visceral adiposity may have value as a biomarker to inform personalized treatment strategies, of even greater impact would be if a therapeutic strategy emerges from the future identification of adipose-derived mediators of this putative anticancer immune-priming effect.
Matthew L. Steinhauser
Sarcoidosis is an inflammatory disease characterized by immune cell–rich granulomas that form in multiple organs. In this issue of the JCI, Sati and colleagues used scRNA-seq and spatial transcriptomics of skin samples from patients with sarcoidosis and non-sarcoidosis granulomatous disease to identify upregulation of a stromal-immune CXCL12/CXCR4 axis and accumulation of type 1 innate lymphoid cells (ILC1s) in sarcoidosis. The accumulation of ILC1s in skin and blood was specific to patients with sarcoidosis and not observed in other granulomatous diseases. The authors used a mouse model of lung granuloma to show that ILCs contribute to granuloma formation and that blockade of CXCR4 reduced the formation of granulomas, providing a proof of concept that sarcoidosis may be treated by CXCR4 blockade to prevent the progression of disease in patients. These results suggest ILC1s could serve as a diagnostic biomarker in sarcoidosis and a potential therapeutic target.
Inchul Cho, Andrew L. Ji
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