Peritoneal dialysis (PD) employs hypertonic glucose to remove excess water and uremic waste. Peritoneal membrane failure limits its long‐term use. T‐cell cytokines promote this decline. T‐cell differentiation is critically determined by the microenvironment. We here study how PD‐range hypertonic glucose regulates T‐cell polarization and IL‐17 production. In the human peritoneal cavity, CD3+ cell numbers increased in PD. Single cell RNA sequencing detected expression of T helper (Th) 17 signature genes RORC and IL23R. In vitro, PD‐range glucose stimulated spontaneous and amplified cytokine‐induced Th17 polarization. Osmotic controls l‐glucose and d‐mannose demonstrate that induction of IL‐17A is a substance‐independent, tonicity dose‐dependent process. PD‐range glucose upregulated glycolysis and increased the proportion of dysfunctional mitochondria. Blockade of reactive‐oxygen species (ROS) prevented IL‐17A induction in response to PD‐range glucose. Peritoneal mesothelium cultured with IL‐17A or IL17F produced pro‐inflammatory cytokines IL‐6, CCL2, and CX3CL1. In PD patients, peritoneal IL‐17A positively correlated with CX3CL1 concentrations. PD‐range glucose‐stimulated, but neither identically treated Il17a−/−Il17f−/− nor T cells cultured with the ROS scavenger N‐acetylcysteine enhanced mesothelial CX3CL1 expression. Our data delineate PD‐range hypertonic glucose as a novel inducer of Th17 polarization in a mitochondrial‐ROS‐dependent manner. Modulation of tonicity‐mediated effects of PD solutions may improve membrane survival.

Cystic fibrosis (CF) is the most common life-limiting monogenetic disease in European populations and is caused by mutations in the CFTR gene. Chronic airway infections with opportunistic pathogens are the major morbidity that determines prognosis and quality of life in most people with CF.

BackgroundComprehensive studies investigated the role of T cells in asthma leading to personalised treatment options targeting severe eosinophilic asthma. However, little is known about the contribution of B cells to this chronic inflammatory disease. In this study, we investigated the contribution of various B cell populations to specific clinical features in asthma.MethodsIn the All Age Asthma Cohort (ALLIANCE) a subgroup of 154 adult asthma patients and 28 healthy controls were included for B cell characterisation by flow cytometry. Questionnaires, lung function measurements, blood differential counts and allergy testing of participants were analysed together with comprehensive data on B cells via association studies and multivariate linear models.ResultsPatients with severe asthma showed decreased immature B cell populations while memory B cells were significantly increased compared to both mild-moderate asthma patients and healthy controls. Furthermore, increased frequencies of immunoglobulin A positive (IgA+) memory B cells were associated with impaired lung function and specifically with parameters indicative for augmented resistance in the peripheral airways. Accordingly, asthma patients with small airway dysfunction (SAD) defined by impulse oscillometry showed increased frequencies of IgA+ memory B cells, particularly in patients with mild to moderate asthma. Additionally, IgA+ memory B cells significantly correlated with clinical features of SAD such as exacerbations.ConclusionsWith this study we demonstrate for the first time a significant association of increased IgA+ memory B cells with asthma and SAD, pointing towards future options for B cell-directed strategies in preventing and treating asthma.

Background: The risk of cardiovascular events rises after acute kidney injury. Leukocytes promote atherosclerotic plaque growth and instability. We have established a model of enhanced remote atherosclerosis after renal ischemia reperfusion (IR) injury and investigate the underlying inflammatory mechanisms. Methods: Atherosclerotic lesions and inflammation were investigated in native and bone marrow-transplanted LDL receptor-deficient (LDLr-/-) mice after unilateral renal IR injury using histology, flow cytometry, and gene expression analysis. Results: Aortic root atherosclerotic lesions were significantly larger after renal IR injury than in controls. A gene expression screen revealed enrichment for chemokines and their cognate receptors in aortas of IR-injured mice in early atherosclerosis, and of T cell-associated genes in advanced disease . Confocal microscopy revealed increased aortic macrophage proximity to T cells. Differential aortic inflammatory gene regulation in IR-injured mice largely paralleled the pattern in the injured kidney. Single-cell analysis identified renal cell types that produced soluble mediators upregulated in the atherosclerotic aorta. The analysis revealed a marked early increase in Ccl2, which CCR2+ myeloid cells mainly expressed. CCR2 mediated myeloid cell homing to the post-ischemic kidney in a cell-individual manner. Reconstitution with Ccr2-/- bone marrow dampened renal post-ischemic inflammation, reduced aortic Ccl2 and inflammatory macrophage marker CD11c, and abrogated excess aortic atherosclerotic plaque formation after renal IR. Conclusions: Our data introduce an experimental model of remote proatherogenic effects of renal IR and delineate myeloid CCR2 signaling as a mechanistic requirement. Monocytes should be considered as mobile mediators when addressing systemic vascular sequelae of kidney injury.