American Journal of Pathology最新文献

Chronic kidney disease (CKD) is a global health concern with high morbidity and mortality. Acute kidney injury (AKI) is a pivotal risk factor for the progression of CKD, and the rate of AKI-to-CKD progression increases with aging. Intrarenal inflammation is a fundamental mechanism underlying AKI-to-CKD progression. Tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates formed in nonlymphoid organs, develop in aged injured kidneys, but not in young kidneys, with prolonged inflammation and maladaptive repair, which potentially exacerbates AKI-to-CKD progression in aged individuals. Dysregulated immune responses are involved in the pathogenesis of various kidney diseases, such as IgA nephropathy, lupus nephritis, and diabetic kidney diseases, thereby deteriorating kidney function. TLSs also develop in several kidney diseases, including transplanted kidneys and renal cell carcinoma. However, the precise immunologic mechanisms driving AKI-to-CKD progression and development of these kidney diseases remain unclear, which hinders the development of novel therapeutic approaches. This review aims to describe recent findings from single-cell analysis of cellular heterogeneity and complex interactions among immune and renal parenchymal cells, which potentially contribute to the pathogenesis of AKI-to-CKD progression and other kidney diseases, highlighting the mechanisms of formation and pathogenic roles of TLSs in aged injured kidneys.

Intrahepatic cholangiocarcinoma (iCCA) denotes a rare, highly malignant, and heterogeneous class of primary liver adenocarcinomas exhibiting phenotypic characteristics of cholangiocyte differentiation. Among the distinctive pathological features of iCCA, one that differentiates the most common macroscopic subtype (eg, mass-forming type) of this hepatic tumor from conventional hepatocellular carcinoma, is a prominent desmoplastic reaction manifested as a dense fibro-collagenous-enriched tumor stroma. Cancer-associated fibroblasts (CAFs) represent the most abundant mesenchymal cell type in the desmoplastic reaction. Although the protumor effects of CAFs in iCCA have been increasingly recognized, more recent cell lineage tracing studies, advanced single-cell RNA sequencing, and expanded biomarker analyses have provided new awareness into their ontogeny, as well as underscored their biological complexity as reflected by the presence of multiple subtypes. In addition, evidence has been described to support CAFs' potential to display cancer-restrictive roles, including immunosuppression. However, CAFs also play important roles in facilitating metastasis, as exemplified by lymph node metastasis and peritoneal carcinomatosis, which are common in iCCA. Herein, the authors provide a timely appraisal of the origins and phenotypic and functional complexity of CAFs in iCCA, together with providing mechanistic insights into lymphangiogenesis and peritoneal metastasis relevant to this lethal human cancer.

Monocyte patrolling of the vasculature has been ascribed primarily to the non-classical monocyte subset. However, a recent study of the glomerular microvasculature provided evidence that both classical and non-classical monocytes undergo periods of intravascular retention and migration. Despite this, whether these subsets contribute differentially to acute glomerular inflammation is unknown. This study used glomerular multiphoton intravital microscopy to investigate the capacity of classical and non-classical monocytes to patrol the glomerular microvasculature and promote acute, neutrophil-dependent glomerular inflammation. In imaging experiments in monocyte reporter Cx3cr1^gfp/+ mice, co-staining with anti-Ly6B or anti-Ly6C revealed that both non-classical monocytes [CX3C chemokine receptor 1-green fluorescent protein positive (CX3CR1-GFP⁺)] and classical monocytes (CX3CR1-GFP⁺ and Ly6B⁺ or Ly6C⁺) underwent prolonged (>10 minutes) retention and migration in the glomerular microvasculature. On induction of acute glomerulonephritis, in these behaviors were increased in classical but not non-classical monocytes. Using non-classical monocyte-deficient Csf1r^CreNr4a1^fl/fl mice, or anti-CCR2 to deplete classical monocytes, the removal of either subset reduced neutrophil retention and activation in acutely inflamed glomeruli, while the depletion of both subsets, via anti-CCR2 treatment in Csf1r^CreNr4a1^fl/fl mice, led to further reductions in neutrophil activity. In contrast, in a model of CD4⁺ T cell-dependent glomerulonephritis, the depletion of either monocyte subset failed to alter neutrophil responses. These findings indicate that both classical and non-classical monocytes patrol the glomerular microvasculature and promote neutrophil responses in acutely inflamed glomeruli.