The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis

Reduced CXCL1 production by endogenous IL-37 expressing dendritic cells does not affect T cell activation.

The dendritic cell (DC)-derived cytokine profile contributes to naive T cell differentiation, thereby directing the immune response. IL-37 is a cytokine with anti-inflammatory characteristics that has been demonstrated to induce tolerogenic properties in DC. In this study we aimed to evaluate the influence of IL-37 on DC-T cell interaction, with a special focus on the role of the chemokine CXCL1. DC were cultured from bone marrow of human IL-37 transgenic (hIL-37Tg) or WT mice. The phenotype of unstimulated and LPS-stimulated DC was analyzed (co-stimulatory molecules and MHCII by flow cytometry, cytokine profile by RT-PCR and ELISA), and T cell stimulatory capacity was assessed in mixed lymphocyte reaction. The role of CXCL1 in T cell activation was analyzed in T cell stimulation assays with anti-CD3 or allogeneic DC. The expression of the co-stimulatory molecules CD40, CD80 and CD86, and of MHCII in LPS-stimulated DC was not affected by endogenous expression of IL-37, whereas LPS-stimulated hIL-37Tg DC produced less CXCL1 compared to LPS-stimulated WT DC. T cell stimulatory capacity of LPS-matured hIL-37Tg DC was comparable to that of WT DC. Recombinant mouse CXCL1 did not increase T cell proliferation either alone or in combination with anti-CD3 or allogeneic DC, nor did CXCL1 affect the T cell production of interferon-γ and IL-17. Endogenous IL-37 expression does not affect mouse DC phenotype or subsequent T cell stimulatory capacity, despite a reduced CXCL1 production. In addition, we did not observe an effect of CXCL1 in T cell proliferation or differentiation

Information Based Aerial Exploration with a Gimballed EO/IR Sensor

In this report we present an exploration framework that is inspired by the research in optimal path for bearings-only tracking. A number of static grid points represent the area to be explored by an aerial sensor platform with a gimballed EO/IR staring array sensor with limited field-of-view. The problem is to plan the path of the sensor platform and the aiming direction of the EO/IR sensor to minimize the uncertainty, in some sense, of the grid points. The objective measures used are based on information theory concepts and can be interpreted as parametric Cramér Rao Bound

Ablation of NLRP3, but not ASC, abrogated IPC protective effects on cardiac function following I/R.

<p>Effect of ASC and NLRP3 gene ablation on cardiac mechanical performance following acute I/R with or without preceding IPC in isolated perfused mouse hearts. (A) End-diastolic pressure (EDP) measured at end reperfusion for the different groups; (B) % Rate-pressure product (RPP) determined at end reperfusion and normalized to baseline, pre-ischemic, values for the different groups. Black bars denote I/R groups, white bars reflect IPC + I/R groups. (n = 7 for all groups). Mean ± SEM, * P<0.05 vs. I/R in WT, ^# P<0.05 IPC+I/R vs. I/R similar group (ANOVA).</p

Unaltered HMGB1 mRNA levels.

<p>Myocardial HMGB1 mRNA levels at end reperfusion for wild-type (WT), ASC^−/− and NLRP3^−/− hearts subjected to ischemia-reperfusion with or without IPC. Black bars denote I/R groups, white bars reflect IPC + I/R groups. (n = 7 for all groups). Mean ± SEM, * P<0.05 vs. I/R in WT (ANOVA).</p

Decreased STAT3 and increased AMPK protein levels in NLRP3^−/− hearts.

<p>Effect of NLRP3 gene ablation on survival kinases and their phosphorylation status in preconditioned hearts analyzed at 5 min reperfusion following 35 min ischemia. PKC-ε (A), ERK (C), AMPK (E) and STAT3 (G), and their phosphorylation status (B, D, F, and H, respectively) are shown (n = 4 hearts per genotype). Mean ± SEM, *P<0.05 WT vs. NLRP3^−/−.</p

Reduced IL-6 cytokine levels in reperfused NLRP3^−/− hearts.

<p>Myocardial cytokine levels at end reperfusion for wild-type (WT), ASC^−/− and NLRP3^−/− hearts subjected to I/R with or without IPC. IL-6 (A), TNF-α (B) and IL-1β (C) are given. Black bars denote I/R groups, white bars reflect IPC + I/R groups. (n = 7 for all groups). Mean ± SEM, * P<0.05 vs. I/R in WT (ANOVA).</p

Ablation of NLRP3, but not ASC, abrogated IPC protective effects on cardiac I/R-induced cell death.

<p>Effects of ASC and NLRP3 gene ablation on cell death (LDH enzyme release) after I/R with or without preceding IPC. Accumulative LDH release during 45 min reperfusion is given for the different groups. Black bars denote I/R groups, white bars reflect IPC + I/R groups. (n = 7 for all groups). Mean ± SEM, * P<0.05 vs. I/R in WT, ^# P<0.05 IPC+I/R vs. I/R similar group (ANOVA).</p

Physiological characteristics of Langendorff-perfused hearts of wild-type (WT), ASC^−/− and NLRP3^−/− mice.

<p>Values are given as (mean ± SEM). EDP: end-diastolic pressure; Psys: peak systolic pressure; HR: heart rate; RPP: rate-pressure-product.</p