TREM1/3 deficiency impairs tissue repair after acute kidney injury and mitochondrial metabolic flexibility in tubular epithelial cells

Long-term sequelae of acute kidney injury (AKI) are associated with incomplete recovery of renal function and the development of chronic kidney disease (CKD), which can be mediated by aberrant innate immune activation, mitochondrial pathology, and accumulation of senescent tubular epithelial cells (TECs). Herein, we show that the innate immune receptor Triggering receptor expressed on myeloid cells-1 (TREM-1) links mitochondrial metabolism to tubular epithelial senescence. TREM-1 is expressed by inflammatory and epithelial cells, both players in renal repair after ischemia/reperfusion (IR)-induced AKI. Hence, we subjected WT and TREM1/3 KO mice to different models of renal IR. TREM1/3 KO mice displayed no major differences during the acute phase of injury, but increased mortality was observed in the recovery phase. This detrimental effect was associated with maladaptive repair, characterized by persistent tubular damage, inflammation, fibrosis, and TEC senescence. In vitro, we observed an altered mitochondrial homeostasis and cellular metabolism in TREM1/3 KO primary TECs. This was associated with G2/M arrest and increased ROS accumulation. Further exposure of cells to ROS-generating triggers drove the cells into a stress-induced senescent state, resulting in decreased wound healing capacity. Treatment with a mitochondria anti-oxidant partly prevented the senescent phenotype, suggesting a role for mitochondria herein. In summary, we have unraveled a novel (metabolic) mechanism by which TREM1/3 deficiency drives senescence in TECs. This involves redox imbalance, mitochondrial dysfunction and a decline in cellular metabolic activities. These finding suggest a novel role for TREM-1 in maintaining tubular homeostasis through regulation of mitochondrial metabolic flexibility

Role of Toll-Like Receptors 2 and 4 in Pulmonary Inflammation and Injury Induced by Pneumolysin in Mice

Background: Pneumolysin (PLN) is an intracellular toxin of Streptococcus pneumoniae that has been implicated as a major virulence factor in infections caused by this pathogen. Conserved bacterial motifs are recognized by the immune system by pattern recognition receptors among which the family of Toll-like receptors (TLRs) prominently features. The primary objective of the present study was to determine the role of TLR2 and TLR4 in lung inflammation induced by intrapulmonary delivery of PLN. Methodology/Results: First, we confirmed that purified PLN activates cells via TLR4 (not via TLR2) in vitro, using human embryonic kidney cells transfected with either TLR2 or TLR4. Intranasal administration of PLN induced an inflammatory response in the pulmonary compartment of mice in vivo, as reflected by influx of neutrophils, release of proinflammatory cytokines and chemokines, and a rise in total protein concentrations in bronchoalveolar lavage fluid. These PLN-induced responses were dependent in part, not only on TLR4, but also on TLR2, as indicated by studies using TLR deficient mice. Conclusion: These data suggest that although purified PLN is recognized by TLR4 in vitro, PLN elicits lung inflammation i

Toll-Like Receptor Family Polymorphisms Are Associated with Primary Renal Diseases but Not with Renal Outcomes Following Kidney Transplantation

Toll-like receptors (TLRs) play a crucial role in innate- and adaptive immunity. The TLR pathways were shown to play key functional roles in experimental acute and chronic kidney injury, including the allo-immune response after experimental renal transplantation. Data about the precise impact of TLRs and their negative regulators on human renal transplant outcomes however are limited and contradictory. We studied twelve non-synonymous single nucleotide polymorphisms (SNPs) of which eleven in TLR1-8 and one in SIGIRR in a final cohort comprising 1116 matching donors and recipients. TLR3 p.Leu412Phe and SIGIRR p.Gln312Arg significantly deviated from Hardy-Weinberg equilibrium and were excluded. The frequency distribution of the minor alleles of the remaining 10 TLR variants were compared between patients with end-stage renal disease (recipients) and controls (kidney donors) in a case-control study. Secondly, the associations between the minor allele frequency of the TLR variants and delayed graft function, biopsy-proven acute rejection and death-censored graft failure after transplantation were investigated with Cox regression. Carrier frequencies of the minor alleles of TLR1 p.His305Leu (OR = 4.79, 95% CI = 2.35-9.75, P = 0.0002), TLR1 p.Asn248Ser (OR = 1.26, 95% CI = 1.07-1.47, P = 0.04) and TLR8 p.Met1Val (OR = 1.37, 95% CI = 1.14-1.64, P = 0.008) were significantly higher in patients with ESRD, with little specificity for the underlying renal disease entity (adjusted for age, gender and donor-recipient relatedness). The minor allele frequency of none of the TLR variants significantly associated with the surrogate and definite outcomes, even when multivariable models were created that could account for TLR gene redundancy. In conclusion, genetic variants in TLR genes were associated with the prevalence of ESRD but not renal transplant outcomes. Therefore, our data suggests that specific TLR signaling routes might play a role in the final common pathway of primary renal injury. A role for TLR signaling in the context of renal transplantation is probably limited

Training compliance control yields improvements in drawing as a function of beery scores

Many children have difficulty producing movements well enough to improve in sensori-motor learning. Previously, we developed a training method that supports active movement generation to allow improvement at a 3D tracing task requiring good compliance control. Here, we tested 7–8 year old children from several 2nd grade classrooms to determine whether 3D tracing performance could be predicted using the Beery VMI. We also examined whether 3D tracing training lead to improvements in drawing. Baseline testing included Beery, a drawing task on a tablet computer, and 3D tracing. We found that baseline performance in 3D tracing and drawing co-varied with the visual perception (VP) component of the Beery. Differences in 3D tracing between children scoring low versus high on the Beery VP replicated differences previously found between children with and without motor impairments, as did post-training performance that eliminated these differences. Drawing improved as a result of training in the 3D tracing task. The training method improved drawing and reduced differences predicted by Beery scores

RAGE does not contribute to renal injury and damage upon ischemia/reperfusion-induced injury.

Item does not contain fulltextThe receptor for advanced glycation end products (RAGE) mediates a variety of inflammatory responses in renal diseases, but its role in renal ischemia/reperfusion (I/R) injury is unknown. We showed that during renal I/R, RAGE ligands HMGB1 and S100B are expressed. However, RAGE deficiency does not affect renal injury and function upon I/R-induced injury

Toll-Like Receptor 2 Impairs Host Defense in Gram-Negative Sepsis Caused by Burkholderia pseudomallei (Melioidosis)

Willem Wiersinga and colleagues find up-regulation of multiple Toll-like receptors (TLRs) in peripheral blood cells of patients with melioidosis. However, only TLR2 had an effect on the immune response in a mouse model

S100A8/A9 Is Not Involved in Host Defense against Murine Urinary Tract Infection

Background: Inflammation is commonly followed by the release of endogenous proteins called danger associated molecular patterns (DAMPs) that are able to warn the host for eminent danger. S100A8/A9 subunits are DAMPs that belong to the S100 family of calcium binding proteins. S100A8/A9 complexes induce an inflammatory response and their expression correlates with disease severity in several inflammatory disorders. S100A8/A9 promote endotoxin-and Escherichia (E.) coli-induced sepsis showing its contribution in systemic infection. The role of S100A8/A9 during a local infection of the urinary tract system caused by E. coli remains unknown. Methodology/Principal Findings: We investigated the contribution of S100A8/A9 in acute urinary tract infection (UTI) by instilling 2 different doses of uropathogenic E. coli transurethrally in wild type (WT) and S100A9 knockout (KO) mice. Subsequently, we determined bacterial outgrowth, neutrophilic infiltrate and inflammatory mediators in bladder and kidney 24 and 48 hours later. UTI resulted in a substantial increase of S100A8/A9 protein in bladder and kidney tissue of WT mice. S100A9 KO mice displayed similar bacterial load in bladder or kidney homogenate compared to WT mice using 2 different doses at 2 different time points. S100A9 deficiency had little effect on the inflammatory responses to E. Coli-induced UTI infection, as assessed by myeloperoxidase activity in bladder and kidneys, histopathologic analysis, and renal and bladder cytokine concentrations. Conclusions: We show that despite high S100A8/A9 expression in bladder and kidney tissue upon UTI, S100A8/A9 does not contribute to an effective host response against E. Coli in the urinary tract syste

Gene expression profiles in murine influenza pneumonia

BACKGROUND: Many in vitro studies have focused on gene expression in influenza-infected leukocytes, lung tissue or cell lines. However, knowledge of in vivo gene expression in these compartments is limited. METHODS: To obtain insight into gene expression profiles during influenza infection, we determined the expression of multiple genes by using a newly developed mouse-specific multiplex ligation-dependent probe amplification assay. RESULTS: The genes involved in inflammation, Toll-like receptor signaling, coagulation, fibrinolysis, cell adhesion, tissue repair and homeostasis were measured in lung tissue, leukocytes in bronchoalveolar lavage fluid and tracheal epithelial cells in mice, before and after intranasal infection with influenza A. Most of the genes investigated were differentially expressed during the course of infection and returned to baseline levels when mice had recovered from the infection. However, expression of several genes remained altered even though mice had completely cleared the virus. CONCLUSION: These data provide the first information on compartmentalized gene expression profiles in the respiratory tract during influenz

Monocyte chemoattractant protein 1 contributes to an adequate immune response in influenza pneumonia

Monocyte chemoattractant protein 1 (MCP-1) and its receptor CCR2 have been shown to play an import role in leukocyte recruitment to sites of infection and inflammation. To investigate the role of MCP-1 during infection with influenza we inoculated wild-type (WT) and MCP-1 knockout (KO) mice with a non-lethal dose of a mouse adapted strain of influenza A. Influenza infection of WT mice resulted in a profound increase in pulmonary MCP-1 levels. MCP-1 KO mice had enhanced weight loss and did not fully regain their body weight during the 14-day observation period. In addition, MCP-1 KO mice demonstrated elevated viral loads 8 days after infection, which was accompanied by reduced leukocyte recruitment into the infected lungs, primarily caused by a diminished influx of macrophages and granulocytes. Moreover, pulmonary levels of IgA were reduced in MCP-1 KO mice. The pulmonary concentrations of tumor necrosis factor-alpha, interleukin-6, macrophage inflammatory protein 2 and interferon-gamma were higher in MCP-1 KO mice. This study shows that MCP-1 contributes to an adequate protective immune response against influenza infection in mic