Journal of Clinical Investigation最新文献

Neurodegeneration, along with amyloid and tau, define the AT(N) framework of Alzheimer's disease that has shaped the development of diagnostics and therapeutics. Yet, biomarker development for neurodegeneration has lagged behind that for amyloid and tau, with limited definition of its heterogeneous microstructural aspects that may each serve as critical measures. In this issue of the JCI, Gong et al. leveraged diffusion MRI to derive a unique measure of axonal injury or axonal density index (ADI). Through cross-sectional and longitudinal analyses, they demonstrated that the ADI has superior performance in detecting, tracking, and predicting clinical impairment compared with prior diffusion MRI methods to evaluate axonal health and standard biomarkers of amyloid and tau. As such, the ADI measure may serve as an important expansion of the neurodegeneration biomarker repertoire.

Although mammals generally demonstrate limited regenerative capacity compared with amphibians, the digit tip retains remarkable regenerative potential, providing a useful model to study successful mammalian regeneration. This process involves coordinated immune cell activity, vascular remodeling, and tissue reconstruction, yet the molecular checkpoints controlling regenerative versus fibrotic outcomes remain poorly understood. In mammals, regeneration of the digit tip (P3) proceeds through myeloid cell migration, early osteoclast-mediated osteolysis of the distal bone, and subsequent blastema-mediated regeneration. Here we test the hypothesis that lymphatic vessels regulate regenerative capacity by modulating local immune cell dynamics and osteoclast function. Using a lymphatic system-specific reporter line, we discovered that lymphatic vessels grow toward the nail region from the ventral side of the digit during quiescence and after amputation. These lymphatics closely surround, but do not invade, the native or regenerated bone. Unexpectedly, genetic, pharmacological, and surgical inhibition of lymphangiogenesis accelerated early osteolysis through enhanced transition of myeloid cells to osteoclasts, resulting in faster and more robust regeneration. These findings reveal a mechanism linking lymphatic vessel, immune regulation, and bone remodeling, suggesting that targeted manipulation of lymphatics dynamics may enhance regenerative outcomes after musculoskeletal injury.

Preclinical data demonstrating that luspatercept mitigates vaso-occlusive and anemia-related complications in the Townes sickle cell model provide a strong rationale for its evaluation in SCD patients.

The regulation of the programmed cell death protein 1 (PD-1) gene, PDCD1, has been widely explored at transcription and posttranslational levels in T cell function and tumor immune evasion. However, the mechanism for PDCD1 dysregulation at the posttranscriptional level remains largely unknown. Here, we identify protein arginine methyltransferase 5 (PRMT5) as a RNA binding protein in a methyltransferase activity-independent manner, which promotes PDCD1 decay with WD repeat domain 77 protein (WDR77) and Argonaute2. Furthermore, the type-I IFN/STAT1 pathway transcriptionally activates PRMT5 and WDR77, thus enhancing PRMT5/WDR77 binding on a conserved AU-rich element of PDCD1 3' UTR. Functionally, conditional knockout of either PRMT5 or WDR77 in T cells disrupts T cell effector function and sensitizes the tumors to anti-PD-1 therapy. Clinically, PRMT5 and WDR77 expression in tumor-infiltrating T cells are negatively correlated with PDCD1 expression and renders tumors resistant to PD-1-targeted immunotherapy. Moreover, fludarabine targeting STAT1 in combination with anti-PD-1 has a synergetic effect on suppressing tumor growth in mice. Overall, this study reveals that the RNA binding-dependent function of PRMT5 regulates PDCD1 and T cell effector function with WDR77 and identifies potential combinatorial therapeutic strategies for enhancing antitumor efficacy.

Human genetic studies have repeatedly associated ADAMTS7 with atherosclerotic cardiovascular disease. Subsequent investigations in mice demonstrated that ADAMTS7 is proatherogenic and induced in response to vascular injury. However, the cell-specific mechanisms governing ADAMTS7 proatherogenicity remain unclear. To determine which vascular cell types express ADAMTS7, we interrogated single-cell RNA sequencing of human carotid atherosclerosis and found ADAMTS7 expression in smooth muscle cells (SMCs), endothelial cells (ECs), and fibroblasts. We subsequently created SMC- and EC-specific Adamts7 conditional knockout and transgenic mice. Conditional knockout of Adamts7 in either cell type does not reduce atherosclerosis, whereas transgenic induction in either cell type increases atherosclerosis. In SMC transgenic mice, this increase coincides with an expansion of lipid-laden SMC foam cells and a decrease in fibrous cap formation. RNA-sequencing in Adamts7 overexpressing SMCs revealed an upregulation of lipid genes typically assigned to macrophages. Mechanistically, ADAMTS7 increases SMC oxLDL uptake through CD36, whose expression is upregulated by PU.1. ATAC-seq and motif analysis revealed increased chromatin accessibility at AP-1 enriched regions, consistent with AP-1 dependent remodeling of PU.1-regulated lipid-handling loci. In summary, ADAMTS7 promotes atherosclerosis by driving SMC foam cell formation through an AP-1/PU.1/CD36 regulatory axis.

How β-Catenin (βCat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role βCat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism, PA) constitutes a major cause of cardiovascular morbidity and is associated with βCat gain-of-function (βCat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin-βCat-α-Catenin complex and mediate aldosterone production. Whether βCat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we showed that aldosterone secretagogues (K+, AngII) and βCat-GOF mediated AJ formation via Rho/ROCK/actomyosin signaling. In addition, Rho/ROCK inhibition led to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific βCat-GOF demonstrated increased AJ formation and zG hyperplasia, which was blunted by Rho/ROCK inhibition and deletion of α-Catenin. βCat also impacted AJ formation independently of its role as a transcription factor. Furthermore, analysis of human aldosterone-producing adenomas revealed high levels of βCat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identified Rho/ROCK signaling and αCat as key mediators of AJ formation and βCat-driven hyperplasia.

Protectin DX (PDX) is a member of the superfamily of specialized proresolving mediators and exerts anti-inflammatory actions in animal models; however, its signaling mechanism remains unclear. Here, we demonstrate the analgesic actions of PDX in a mouse model of tibial fracture-induced postoperative pain (fPOP). Intravenous early- and late-phase treatment of PDX (100 ng/mouse) effectively alleviated fPOP. Compared with protectin D1 (PD1)/neuroprotectin D1, DHA, steroids, and meloxicam, PDX provided superior pain relief. While dexamethasone and meloxicam prolonged fPOP, PDX shortened the pain duration. The analgesic effects of PDX were abrogated in Gpr37-/- mice, which displayed deficits in fPOP resolution. PDX was shown to bind GPR37 and induce calcium responses in peritoneal macrophages. LC-MS/MS-based lipidomic analysis revealed that endogenous PDX levels were approximately 10-fold higher than those of PD1 in muscle at the fracture site. PDX promoted macrophage polarization via GPR37-dependent phagocytosis and efferocytosis through calcium signaling in vitro, and it further enhanced macrophage viability and efferocytosis in vivo via GPR37. Finally, PDX rapidly modulated nociceptor neuron responses by suppressing C-fiber-induced muscle reflex in vivo and calcium responses in DRG neurons ex vivo and by reducing TRPA1/TRPV1-induced acute pain and neurogenic inflammation in vivo. Our findings highlight multiple benefits of PDX to manage postoperative pain and promote perioperative recovery.