Itamar Goren - Academia.edu (original) (raw)

Papers by Itamar Goren

npj Regenerative Medicine

Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induc... more Murine acetaminophen-induced acute liver injury (ALI) serves as paradigmatic model for drug-induced hepatic injury and regeneration. As major cause of ALI, acetaminophen overdosing is a persistent therapeutic challenge with N-acetylcysteine clinically used to ameliorate parenchymal necrosis. To identify further treatment strategies that serve patients with poor N-acetylcysteine responses, hepatic 3′mRNA sequencing was performed in the initial resolution phase at 24 h/48 h after sublethal overdosing. This approach disclosed 45 genes upregulated (≥5-fold) within this time frame. Focusing on C5aR1, we observed in C5aR1-deficient mice disease aggravation during resolution of intoxication as evidenced by increased liver necrosis and serum alanine aminotransferase. Moreover, decreased hepatocyte compensatory proliferation and increased caspase-3 activation at the surroundings of necrotic cores were detectable in C5aR1-deficient mice. Using a non-hypothesis-driven approach, herein pro-rege...

If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting sk... more If insufficiently treated, Lyme borreliosis can evolve into an inflammatory disorder affecting skin, joints, and the CNS. Early innate immunity may determine host responses targeting infection. Thus, we sought to characterize the immediate cytokine storm associated with exposure of PBMC to moderate levels of live Borrelia burgdorferi. Since Th17 cytokines are connected to host defense against extracellular bacteria, we focused on interleukin (IL)-17 and IL-22. Here, we report that, despite induction of inflammatory cytokines including IL-23, IL-17 remained barely detectable in response to B. burgdorferi. In contrast, T cell-dependent expression of IL-22 became evident within 10 h of exposure to the spirochetes. This dichotomy was unrelated to interferon-c but to a large part dependent on caspase-1 and IL-1 bioactivity derived from monocytes. In fact, IL-1b as a single stimulus induced IL-22 but not IL-17. Neutrophils display antibacterial activity against B. burgdorferi, particularl...

ABSTRACTSystemic inflammation is associated with alterations in complex brain functions such as l... more ABSTRACTSystemic inflammation is associated with alterations in complex brain functions such as learning and memory. However, diagnostic approaches to functionally assess and quantify inflammation-associated alterations in synaptic plasticity are not well-established. In previous work, we demonstrated that bacterial lipopolysaccharide (LPS)-induced systemic inflammation alters the ability of hippocampal neurons to express synaptic plasticity, i.e., the long-term potentiation (LTP) of excitatory neurotransmission. Here, we tested whether synaptic plasticity induced by repetitive magnetic stimulation (rMS), a non-invasive brain stimulation technique used in clinical practice, is affected by LPS-induced inflammation. Specifically, we explored brain tissue cultures to learn more about the direct effects of LPS on neural tissue, and we tested for the plasticity-restoring effects of the anti-inflammatory cytokine interleukin 10 (IL10). As shown previously, 10 Hz repetitive magnetic stimul...

American journal of physiology. Renal physiology, Jan 8, 2017

Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal time course causes impairm... more Deficiency of cyclooxygenase-2 (COX-2) activity in the early postnatal time course causes impairment of kidney development leading to kidney insufficiency. We hypothesize that impaired NaCl reabsorption during the first days of life is a substantial cause for nephrogenic defects observed in COX-2-/- mice and that salt supplementation corrects these defects. Daily injections of 0.8 mg/g/d NaCl for the first 10 days after birth ameliorated impaired kidney development in COX-2-/- pups resulting in an increase in glomerular size and reduction of immature superficial glomeruli. However, impaired renal subcortical growth was not corrected. Increasing renal tubular flow by volume load or injections of KCl did not relieve the renal histomorphological damage. Administration of torsemide and spironolacton also affected nephrogenesis resulting in diminished glomeruli and cortical thinning. Treatment of COX-2-/- pups with NaCl/DOCA caused a stronger mitigation of glomerular size and also induce...

Virology, 1999

In this work we examine the role of three genetic control components in the regulation of HTLV-1 ... more In this work we examine the role of three genetic control components in the regulation of HTLV-1 transcription: cyclic AMP-responsive element (CRE)-binding protein (CREB), the HTLV-1 trans-activator Tax, and the three Tax-responsive elements (TREs). We demonstrate that the in vivo efficiency of the HTLV-1 promoter basal expression in cell culture depends on the spacing between the three TRE elements, located at the HTLV-1 LTR (long terminal repeat), whereas the level of transcription activation mediated by Tax is affected by the number of TREs. In the presence of only one TRE, the enhancement of expression by Tax is affected by the distance between the single TRE and the transcription start site. Following CREB binding to the LTR, additional DNase I hypersensitive sites are generated in the region between the two distal TREs (I and II), while in the presence of Tax, such sites are generated also in the region between TREs II and III. Neither cooperative binding of CREB to the TREs nor preferential binding of CREB to a particular TRE was observed. Tax binding to the CREB/TRE complex does not change the DNase I protection pattern. Taken together, these results suggest that the basal CREB-mediated transcription is determined by the number and the position of the viral TREs relative to each other. Tax protein stabilizes the protein/DNA complex and suppresses the spacing limitations, probably by bridging between the CREB/TRE complexes and the basal initiation transcription complex.

Kidney International, 2008

Biochemical and Biophysical Research Communications, 2014

Type-2 diabetes mellitus (T2D) represents an important metabolic disorder, firmly connected to ob... more Type-2 diabetes mellitus (T2D) represents an important metabolic disorder, firmly connected to obesity and low level of chronic inflammation caused by deregulation of fat metabolism. The convergence of chronic inflammatory signals and nutrient overloading at the endoplasmic reticulum (ER) leads to activation of ER-specific stress responses, the unfolded protein response (UPR). As obesity and T2D are often associated with impaired wound healing, we investigated the role of UPR in the pathologic of diabeticimpaired cutaneuos wound healing. We determined the expression patterns of the three UPR branches during normal and diabetes-impaired skin repair. In healthy and diabetic mice, injury led to a strong induction of BiP (BiP/Grp78), C/EBP homologous protein (CHOP) and splicing of X-box-binding protein (XBP)1. Diabetic-impaired wounds showed gross and sustained induction of UPR associated with increased expression of the pro-inflammatory chemokine macrophage inflammatory protein (MIP)2 as compared to normal healing wounds. In vitro, treatment of RAW264.7 macrophages with tunicamycin, and subsequently stimulation with lipopolysaccharide (LPS) and interferon (IFN)-c enhances MIP2 mRNA und protein expression compared to proinflammatory stimulation alone. However, LPS/IFNc induced vascular endothelial growth factor (VEGF) production was blunted by tunicamycin induced-ER stress. Hence, UPR is activated following skin injury, and functionally connected to the production of proinflammatory mediators. In addition, prolongation of UPR in diabetic non-healing wounds aggravates ER stress and weakens the angiogenic phenotype of wound macrophages.

Biochemical and Biophysical Research Communications, 2008

American Journal of Respiratory Cell and Molecular Biology, 2011

High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilat... more High-pressure ventilation induces barotrauma and pulmonary inflammation, thus leading to ventilator-induced lung injury (VILI). IL-22 has both immunoregulatory and tissue-protective properties. Functional IL-22 receptor expression is restricted to nonleukocytic cells, such as alveolar epithelial cells. When applied via inhalation, IL-22 reaches the pulmonary system directly and in high concentrations, and may protect alveolar epithelial cells against cellular stress and biotrauma associated with VILI. In A549 lung epithelial cells, IL-22 was able to induce rapid signal transducer and activator of transcription (STAT)-3 phosphorylation/activation, and hereon mediated stable suppressor of cytokine signaling (SOCS) 3 expression detectable even 24 hours after onset of stimulation. In a rat model of VILI, the prophylactic inhalation of IL-22 before induction of VILI (peak airway pressure 5 45 cm H 2 O) protected the lung against pulmonary disintegration and edema. IL-22 reduced VILI-associated biotrauma (i.e., pulmonary concentrations of macrophage inflammatory protein-2, IL-6, and matrix metalloproteinase 9) and mediated pulmonary STAT3/SOCS3 activation. In addition, despite a short observation period of 4 hours, inhaled IL-22 resulted in an improved survival of the rats. These data support the hypothesis that IL-22, likely via activation of STAT3 and downstream genes (e.g., SOCS3), is able to protect against cell stretch and pulmonary baro-/biotrauma by enhancing epithelial cell resistibility.

The American journal of pathology, 2014

The determination of regenerative wound-healing macrophages as alternatively activated macrophage... more The determination of regenerative wound-healing macrophages as alternatively activated macrophages is currently questioned by the absence of IL-4 in wound tissue. Yet, murine wound tissue expressed high levels of Ym1 (chitinase 3-like 3), an established marker of the IL-4-induced alternatively activated macrophage phenotype. Ym1 was expressed in wound neutrophils but not in macrophages. Initially, Ym1-free wound-healing macrophages, invading from the wound margins, became gradually positive for the protein in the absence of IL-4 signaling and Stat6 activation, as they entered the neutrophil-populated wound regions. IL-4 failed to induce Ym1 protein in ex vivo-cultured wound tissue explants containing wound-healing macrophages. Recombinant Ym1 protein was selectively taken up by macrophages but not by keratinocytes and endothelial cells. Cultured macrophages lost the ability to take up the recombinant protein when four highly conserved residues and the 70-amino acid small α+β domain ...

Journal of Investigative Dermatology, 2007

To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importa... more To date, diabetes-associated skin ulcerations represent a therapeutic problem of clinical importance. The insulin-resistant type II diabetic phenotype is functionally connected to obesity in rodent models of metabolic syndrome through the release of inflammatory mediators from adipose tissue. Here, we used the impaired wound-healing process in obese/obese (ob/ob) mice to investigate the impact of obesity-mediated systemic inflammation on cutaneous wound-healing processes. Systemic administration of neutralizing monoclonal antibodies against tumor necrosis factor (TNF)a (V1q) or monocyte/macrophage-expressed EGF-like modulecontaining mucin-like hormone receptor-like (Emr)-1 (F4/80) into wounded ob/ob mice at the end of acute wound inflammation initiated a rapid and complete neo-epidermal coverage of impaired wound tissue in the presence of a persisting diabetic phenotype. Wound closure in antibody-treated mice was paralleled by a marked attenuation of wound inflammation. Remarkably, anti-TNFaand anti-F4/80-treated mice exhibited a strong reduction in circulating monocytic cells and reduced numbers of viable macrophages at the wound site. Our data provide strong evidence that anti-TNFa therapy, widely used in chronic inflammatory diseases in humans, might also exert effects by targeting ''activated'' TNFa-expressing macrophage subsets, and that inactivation or depletion of misbehaving macrophages from impaired wounds might be a novel therapeutic clue to improve healing of skin ulcers.