Biology subjects

Herrlich, A.

Publications and source records attributed to Herrlich, A..

4 recordsLinked to original sources

bioRxiv2024

Sterile kidney tissue injury induces neutrophil swarming in lung alveolar capillaries

Sterile acute kidney injury (AKI) is common in the clinic and frequently associated with hypoxemia that does not improve with dialysis and remains incompletely understood. AKI induces remote lung inflammation with neutrophil recruitment in mice and humans, but which cellular cues establish neutrophilic inflammation and how it contributes to hypoxemia is not known. Here we report that AKI induces rapid intravascular neutrophil retention in lung alveolar capillaries without any significant extravasation into tissue or alveoli, causing hypoxemia by reducing lung capillary blood flow in the absence of any significant lung interstitial or alveolar edema. In contrast to direct ischemic lung injury, lung neutrophil recruitment during remote lung inflammation did not require cues from intravascular non-classical monocytes or tissue-resident alveolar macrophages. Instead, lung neutrophil retention depended on neutrophil chemoattractant CXCL2 released by activated intravascular classical monocytes. Comparative single-cell RNA-sequencing analysis of direct and remote lung inflammation revealed that alveolar macrophages are highly activated and produce the neutrophil chemoattractant CXCL2 only in direct lung inflammation. Establishing a CXCL2 gradient into the alveolus by intratracheal administration of CXCL2 during AKI-induced remote lung inflammation enabled neutrophils to extravasate. We thus discovered important differences in lung neutrophil recruitment in direct versus remote lung inflammation and identified lung capillary neutrophil retention that negatively affects oxygenation by causing a ventilation-perfusion mismatch as a novel driver of AKI-induced hypoxemia.

physiology↗

bioRxiv2023

Acute kidney injury-induced circulating TNFR1/2 elevations correlate with persistent kidney injury and progression to fibrosis

BackgroundElevated levels of circulating Tumor-Necrosis-Factor-Receptors 1 and 2 (cTNFR1/2) predict CKD progression. Whether acute kidney injury drives cTNFR1/2 elevations and whether they predict disease outcomes after AKI remains unknown. MethodsWe used AKI patient serum and urine samples, mouse models of kidney injury (ischemic, obstructive, toxic) and progression to fibrosis, nephrectomy, and related single cell RNA-sequencing datasets. ResultsWe show that TNFR1/2 serum and urine levels are highly elevated in all mouse models of kidney injury tested, beginning within one-hour post-injury, and correlate with its severity. Consistent with this, serum and urine TNFR1/2 levels are increased in AKI patients and correlate with severity of kidney failure. Interestingly, the extracellular vesicle (EV)-bound forms of cTNFR1/2 correlate with renal function better than their soluble forms. TNF neutralization does not affect early cTNFR1/2 elevations, suggesting that cTNFR1/2 levels do not reflect injury-induced TNF activity. Kidney tissue expression of TNFR1/2 after AKI is only mildly increased and bilateral nephrectomies lead to strong cTNFR1/2 elevations, suggesting release of these receptors by extrarenal sources. cTNFR1/2 remain elevated for weeks after severe kidney injury and at these later timepoints cTNFR1/2 correlate to remaining kidney injury. During AKI-to-CKD transition, kidney expression of TNFR1/2 and cTNFR2 levels, correlate with development of fibrosis. ConclusionsOur data demonstrate that AKI drives acute increases in cTNFR1/2 serum levels which negatively correlate with kidney function, in particular their EV-bound forms. Sustained TNFR1/2 elevations after kidney injury during AKI-to-CKD transition correlate with persistent tissue injury and progression to kidney fibrosis. Significance StatementCirculating TNF-Receptor-1 and -2 (cTNFR1/2) elevations predict chronic kidney disease progression. It remains unknown whether kidney injury can drive cTNFR1/2 elevations, whether cTNFR1/2 levels predict disease outcomes after AKI, and which are their circulating molecular forms. This study shows that kidney injury strongly increases cTNFR1/2 levels and that their extracellular vesicle-bound forms better correlate with kidney function loss, compared to their soluble forms. Sustained cTNFR1/2 elevations correlate to remaining kidney injury, and cTNFR1/2 levels post injury predict progression to kidney fibrosis. This work, thus, points to novel mechanisms for the observed cTNFR1/2 elevations in kidney disease and identifies unique predictive and diagnostic value in cTNFR1/2 elevations in AKI or AKI-to-CKD transition.

physiology↗

bioRxiv2021

Circulating osteopontin released by injured kidneys causes pulmonary inflammation and edema

Multiorgan failure is devastating, and its mechanisms and mediators are not clear. Tissue injury in one organ appears to trigger disease in remote organs. Kidney and lung are frequently affected, such as when acute kidney injury (AKI) causes acute lung injury (ALI), a frequent clinical condition with high mortality. Here we identify factors secreted from the injured kidney that cause acute lung injury. We developed a murine model mimicking the generation of respiratory failure following acute kidney injury. To identify interorgan crosstalk mediators involved, we performed scRNAseq of mouse kidneys and lungs after AKI. We then applied ligand-receptor (L-R) pairing analysis across cells residing in kidney (ligands) or lung (receptors) to identify kidney-released circulating osteopontin (OPN) as a novel mediator of AKI-induced ALI (AKI-ALI). OPN release very early after AKI largely from tubule cells triggered neutrophil and macrophage infiltration into lungs associated with endothelial leakage, interstitial edema, and functional impairment. Pharmacological or genetic inhibition of OPN prevented AKI-ALI. Transplantation of ischemic wt kidneys into wt mice caused AKI-ALI, while transplantation of ischemic OPN-global-knockout kidneys failed to induce lung endothelial leakage and AKI-ALI, identifying circulating kidney-released OPN as sufficient to cause AKI-ALI in vivo. We show that AKI in humans results in elevations in OPN levels in the serum. Increased serum OPN levels in patients with multiorgan failure have been shown to positively correlate with reduced kidney function, respiratory failure, and mortality. Thus, our results identifying OPN as a mediator of AKI-ALI may have important therapeutic implications in human AKI-ALI and multiorgan failure.

cell biology↗

bioRxiv2021

TNF drives AKI-to-CKD transition downstream of proximal tubule EGFR

Proximal-tubule-cell EGFR activation mediates tubule cell proliferation and repair early after kidney injury, while sustained EGFR activation causes kidney fibrosis. Inflammation is a key driver of AKI-to-CKD transition and fibrosis, but mechanisms of EGFR-driven profibrotic responses are not well understood. In a mouse model of AKI-to-CKD transition and CKD progression, we show that EGFR-inhibition significantly reduced kidney expression of many immunoregulatory molecules already by day two after injury, including the potent inflammatory cytokine tumor-necrosis-factor (TNF). Single nuclei RNA-sequencing analysis showed that macrophages were among the main early cellular sources of TNF in the injured kidney. In vitro, EGFR activation in macrophages increased macrophage TNF expression, while EGFR inhibition in vivo reduced kidney macrophage accumulation, as early as two days after injury. Thus, profibrotic EGFR signaling increases kidney TNF levels both directly and indirectly. TNF inhibition did not alter tubule EGFR activation and in contrast to EGFR inhibition did not reduce early macrophage accumulation in the kidney, suggesting that TNF does not promote early infiltration of immune cells in the kidney, but rather regulates profibrotic functions of kidney and/or immune cells. TNF inhibition with etanercept in vivo in AKI-injured mice downregulated a number of cytokines, including TNF itself. This cytokine downregulation overlapped with EGFR inhibition, and additional non-overlapping downregulated cytokines shared the same functions, predicting that TNF inhibition would prevent AKI-to-CKD transition like EGFR inhibition. Indeed, TNF-inhibition with etanercept reduced AKI-induced fibrosis to the same degree as the EGFR-inhibition, while the combination of both treatments showed no additive effect. In conclusion, our results identify TNF as a downstream effector of profibrotic EGFR activation and motivate the examination of TNF pathway inhibition in human AKI or CKD. Translational statementProximal tubule epidermal-growth-factor (EGFR) activation in mice and likely also in humans drives inflammation in the kidney after acute-kidney-injury (AKI) and causes chronic-kidney-disease (CKD) with fibrosis in a process termed AKI-to-CKD transition. Recent retrospective data shows that patients treated with TNF inhibitors show decreased incidence and progression of CKD. Our current work shows that TNF inhibition in mice is equally as effective as EGFR inhibition in preventing AKI-to-CKD transition and fibrosis. Thus, our results have translational potential and may stimulate examination of short-term TNF inhibition in AKI to prevent AKI-to-CKD transition or possibly of longer-term TNF inhibition in CKD to prevent CKD progression.

cell biology↗