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Due to the urgent need to create appropriate treatment techniques, which are currently unavailable, LPS-induced sepsis has become a serious concern on a global scale. The primary active component in the pathophysiology of inflammatory diseases such as sepsis is the Gram-negative bacterial lipopolysaccharide (LPS). LPS interacts with cell surface TLR4 in macrophages, causing the formation of reactive oxygen species (ROS), TNF-α, IL-1β and oxidative stress. It also significantly activates the MAPKs and NF-κB pathway. Excessive production of pro-inflammatory cytokines is one of the primary characteristic features in the onset and progression of inflammation. Cytokines mainly signal through the JAK/STAT pathway. We hypothesize that blocking of TLR4 along with TNFR1 might be beneficial in suppressing the effects of STAT1/STAT3 due to the stimulation of SOCS3 proteins. Prior to the LPS challenge, the macrophages were treated with antibodies against TLR4 and TNFR1 either individually or in combination. On analysis of the macrophage populations by flowcytometry, it was seen that receptor blockade facilitated the phenotypic shift of the M1 macrophages towards M2 resulting in lowered oxidative stress. Blocking of TLR4/TNFR1 upregulated the SOCS3 and mTOR expressions that enabled the transition of inflammatory M1 macrophages towards the anti-inflammatory M2 phenotype, which might be crucial in curbing the inflammatory responses. Also the reduction in the production of inflammatory cytokines such as IL-6, IL-1β due to the reduction in the activation of the STAT1 and STAT3 molecules was observed in our combination treatment group. All these results indicated that neutralization of both TLR4 and TNFR1 might provide new insights in establishing an alternative therapeutic strategy for LPS-sepsis.

Summary: Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individual's outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kβ dependent in VGluT2 + INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

TNFα inhibitors have been successfully developed and used in the clinical treatment of autoimmune disorders. However, the use of TNFα blockade may be accompanied by side effects. The cases of bacterial and viral infections, lymphoproliferative disorders, and anti-TNFα-induced lupus, have been reported among the rheumatoid arthritis or Crohn's disease patients treated with TNFα blockers. Therefore, alternative therapeutic strategy is highly desirable. TNFα signaling via TNFR1 induces proinflammatory responses, and selective inhibition of TNFR1 signaling may be beneficial for managing autoimmune diseases. To this end, we developed minibinder proteins targeting soluble ectodomain of TNFR1 (sTNFR1) by de novo computational designing. Top-rated designed minibinders targeting to two hydrophobic sites on sTNFR1 were selected and expressed in E. coli. Purified top-ranked minibinders are thermostable in solution and presented micromolar to sub-micromolar affinity to sTNFR1. All designs showed the potency of blocking TNFα signaling in L929 cell-based assays, and one of the designs targeting to hydrophobic Site I called S1B2 exhibited higher potency than other minibinders with IC 50 of 4.32 nM. Our work provided a new approach to develop TNFR1 antagonist and S1B2 should be a promising lead molecule of TNFR1 antagonist for further development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Aims: While enhanced tumor cell migration is a key process in the tumor dissemination, mechanistic insights into causal relationships between tumor cells and mechanical confinement are still limited. Here we combine the use of microfluidic platforms to characterize confined cell migration with genomic tools to systematically unravel the global signaling landscape associated with the migratory phenotype of breast cancer (BC) cells., Meterials and Methods: The spontaneous migration capacity of seven BC cell lines was evaluated in 3D microfluidic devices and their migration capacity was correlated with publicly available molecular signatures. The role of identified signaling pathways on regulating BC migration capacity was determined by receptor stimulation through ligand binding or inhibition through siRNA silencing. Downstream effects on cell migration were evaluated in microfluidic devices, while the molecular changes were monitored by RT-qPCR., Key Findings: Expression of 715 genes was correlated with BC cells migratory phenotype, revealing TNF-α as one of the top upstream regulators. Signal transduction experiments revealed that TNF-α stimulates the confined migration of triple negative, mesenchymal-like BC cells that are also characterized by high TNFR1 expression, but inhibits the migration of epithelial-like cells with low TNFR1 expression. TNFR1 was strongly associated with the migration capacity and triple-negative, mesenchymal phenotype. Downstream of TNF/TNFR1 signaling, transcriptional regulation of NFKB seems to be important in driving cell migration in confined spaces., Significance: TNF-α/TNFR1 signaling axis reveals as a key player in driving BC cells confined migration, emerging as a promising therapeutic strategy in targeting dissemination and metastasis of triple negative, mesenchymal BC cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Radiation therapy for the management of intrahepatic malignancies can adversely affect liver function. Liver damage has been associated with increased levels of inflammatory cytokines, including tumor necrosis factor alpha (TNFα). We hypothesized that an inflammatory state, characterized by increased soluble TNFα receptor (sTNFR1), mediates sensitivity of the liver to radiation. Materials/Methods: Plasma samples collected during 3 trials of liver radiation for liver malignancies were assayed for sTNFR1 level via enzyme-linked immunosorbent assay (ELISA). Univariate and multivariate logistic regression and longitudinal models were used to characterize associations between liver toxicity (defined as a ≥2-point increase in Child-Pugh [CP] score within 6 months of radiation treatment) and sTNFR1 levels, ALBI score, biocorrected mean liver dose (MLD), age, and baseline laboratory values. Results: Samples from 78 patients given liver stereotactic body radiation therapy [SBRT] (92%) or hypofractionated radiation were examined. There was a significant association between liver toxicity and sTNFR1 levels, and higher values were associated with increased toxicity over a range of mean liver doses. When ALBI score and biocorrected dose were included in the model with sTNFR1, baseline ALBI score and change in ALBI (ΔALBI) were significantly associated with toxicity, but sTNFR1 was not. Baseline aminotransferase levels also predicted toxicity but not independently of ALBI score. Conclusions: Elevated plasma sTNFR1 levels are associated with liver injury after liver radiation, suggesting that elevated inflammatory cytokine activity is a predictor of radiation-induced liver dysfunction. Future studies should determine whether administration of agents that decrease inflammation prior to treatment is warranted.

Dysfunction of endothelial cells (EC) is important for atherosclerosis progression. The aim of this study was to evaluate the potential of ginger extract (GEx), 6-gingerol (6-G) and 6-shogaol (6-Sh) to reverse EC dysfunction and to investigate its mechanism of action, using cultured human EC incubated with TNFα. The results showed that GEx decreases monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and monocyte adhesion. This decrease was associated with the: (1) decrease of ninjurin-1 expression; (2) reduction of TNFα receptor1 and of the receptor for advanced glycation end-products expression (RAGE), in parallel with the increase of soluble RAGE; (3) decrease of NADPH oxidase subunits expression; (4) activation of antioxidant Nrf2 and heme oxygenase-1, and (5) inhibition of NF-kB. The benefic effects of 6-G and 6-Sh were weaker than those of GEx (GEx > 6-Sh > 6-G). In conclusion, GEx might be a promising alternative to ameliorate disorders in which oxidative stress and inflammation are important.

Introduction: Tumor necrosis factor (TNF)-α is a pro-inflammatory cytokine that promotes biomineralization in vitro in dental pulp cells. However, the role of TNF-α-TNF receptor 1 (TNFR1) signaling in reparative dentin formation and related inflammatory pathways is not known. Therefore, the aim of this study was to evaluate the role of the TNF-α-TNFR1 axis in dental pulp repair following pulp capping in vivo., Methods: Dental pulp repair response of genetically deficient TNF-α receptor-1 mice (TNFR1 -/- ; n = 20) was compared with that of C57Bl6 mice (wild type [WT]; n = 20). Pulp capping was performed with mineral trioxide aggregate on the mandibular first molars of mice. After 7 and 70 days, tissues were collected and stained with hematoxylin and eosin for histopathological and histometric evaluation, and assessed by the Brown and Brenn methods for histomicrobiological analysis and by immunohistochemistry to localize TNF-α, Runt-related transcription factor 2, Dentin Sialoprotein (DSP) and Osteopontin (OPN) expression., Results: Compared with WT mice, TNFR1 -/- mice showed significantly decreased reparative dentin formation with a lower mineralized tissue area (P < .0001). Unlike WT mice, TNFR1 -/- mice also exhibited significant dental pulp necrosis, neutrophil recruitment, and apical periodontitis formation (P < .0001) without bacterial tissue invasion. TNFR1 -/- animals further exhibited decreased TNF-α, DSP, and OPN expression (P < .0001), whereas Runt-related transcription factor 2 expression was unchanged (P > .05)., Conclusion: The TNF-α-TNFR1 axis is involved in reparative dentin formation following dental pulp capping in vivo. Genetic ablation of TNFR1 modified the inflammatory process and inhibited the expression of the DSP and OPN mineralization proteins, which culminated in dental pulp necrosis and development of apical periodontitis., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

Introduction: The aim of this study was to investigate the role of the proinflammatory axis TNF-α-TNFR1 in experimentally induced periapical inflammation and bone resorption in mice., Methods: After receiving Ethics Committee Approval (2019.1.139.58.0), experimental apical periodontitis was induced by means of inoculating oral microorganisms into the root canals of molars of mice. Genetically deficient tumor necrosis factor-α receptor-1 mice (TNFR1 -/- ; n = 50) response was compared with that of C57Bl6 wild-type mice (wild-type; n = 50) after 7, 14, 28, and 42 days. The analyses performed were micro-computed tomographic, histopathologic, histomicrobiological, and histometric evaluation, tartrate-resistant acid phosphatase staining, immunohistochemistry, and quantitative reverse transcriptase polymerase chain reaction. Data were analyzed by using one-way analysis of variance, followed by Tukey or Bonferroni tests (α = 5%)., Results: TNFR1 -/- mice exhibited lower recruitment of neutrophils at 14, 28, and 42 days (P < .05), which resulted in reduced area and volume of apical periodontitis at 42 days (P < .05). The number of osteoclasts was also lower in TNFR1 -/- animals at 14 and 42 days (P < .01), along with reduced synthesis of CTSK, MMP-9, and COX-2. Expression of RANKL, but not OPG, was reduced at 14 and 42 days (P < .001). The highest RANKL expression over OPG (ratio > 1) was found in wild-type animals at 7 (P < .0001) and 42 days (P < .001)., Conclusions: Periapical inflammation and bone resorption were exacerbated in wild-type animals compared with TNFR1 -/- mice, demonstrating that the TNF-α-TNFR1 signaling pathway mediated catabolic events in bone after root canal contamination., (Copyright © 2023 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.)

The authors used a method quantitative estimation density of TNFR1/TNFR2 on cells by flow cytometry with calibration particles, which allowed them to estimate the absolute number of receptors on cells regardless of the type of flow cytometer. The TNF receptor expression parameters were used to determine their association with the fact of disease and to build diagnostic models. The proposed methodological approach using a combination of flow cytometry and mathematical modeling techniques represents a promising direction for testing the diagnostic and prognostic significance of the studied biomarkers. The multifactorial regression analysis constructed on the basis of this approach made it possible to refine and supplement diagnostic schemes for determining the probability of rheumatoid arthritis and bronchial asthma in patients., Competing Interests: Declaration of Competing Interest The authors have no financial conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

TNF-α overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-α in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-α and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage. The involvement of TNF-α was further confirmed by the protective effect of treatment with rhTNF-α binding protein (rhTBP-1) from 4 to 9 weeks of age. rhTBP-1 reduced the progression of symptoms, motor neuron loss, gliosis and JNK/p38MAPK phosphorylation in wobbler mice, but did not reduce TNF-α and TNFR1 levels. rhTBP-1 might possibly bind TNF-α and reduce the downstream phosphorylation of two main effectors of the neuroinflammatory response, p38MAPK and JNK.

Soluble TNF receptors (sTNFR1 and sTNFR2) are natural endogenous inhibitors of TNF and are elevated in inflammatory, autoimmune, and chronic degenerative diseases. In Chagas disease, pleiotropic cytokine TNF is considered key in immunopathology. Thus, we aimed to evaluate the levels of TNF, sTNFR1, and sTNFR2 in the serum of patients with chronic Chagas disease. TNF and its soluble receptors were quantified using Cytometric Bead Array in the serum of 132 patients, of which 51 had the indeterminate form (IND), 39 the mild cardiac form (CARD 1), 42 the severe cardiac form (CARD 2), and 20 non-infected individuals (NI). The results indicate that the soluble receptors may regulate TNF in Chagas disease, as their leves were higher in T. cruzi-infected individuals when compared to non-infected individuals. We found a moderate negative correlation between sTNFR1 and TNF in individuals with the IND form, suggesting a relationship with non-progression to more severe forms, such as heart disease. sTNFR1 and sTNFR2 were increased in all clinical forms, but with a moderate positive correlation in more severe patients (r = 0.50 and p = 0.0005). TNF levels showed no statistical differences in the groups of patients. These findings suggest the importance of the endogenous balance of the levels of soluble TNF receptors in the protection and balance in patients with chronic Chagas disease, besides revealing the immunological complexity in chronic T. cruzi-infected individuals., (Copyright © 2021. Published by Elsevier GmbH.)

After sciatic nerve injury, Schwann cells in the distal segments of injury site undergo apoptosis and meanwhile proliferation. Although apoptosis-induced proliferation (AiP) has been characterized in various models, whether the proliferation of Schwann cells in the distal segments is triggered by apoptosis remains unelucidated. In this study, we used small interfering RNA to knock down the expression of TNFR1 and TNFR2 in primarily cultured Schwann cells, respectively and observed its effects on apoptosis and proliferation. The downregulation of TNFR1 or TNFR2 resulted in a remarkable decrease of cell viability and dramatically increased the apoptosis of Schwann cells. In contrast, the cell apoptosis induced by the knockdown of TNFR2, but not TNFR1, promoted the Schwann cell proliferation. Together, these observations indicated that Schwann cells can undergo AiP, and TNFR2 knockdown triggers the process. Additionally, we established the sciatic nerve injury model on TNF-α knock-out (KO) mice, and found that the Schwann cells of KO mice occurred significantly less apoptosis and proliferation than that of wild-type mice in the distal segments, which indicated TNF-α and its receptors were essential in the massive apoptosis and the apoptosis-induced proliferation of Schwann cells after sciatic nerve injury. The finding of AiP in Schwann cells may be beneficial to develop new approaches to promote axon regeneration and thereby improve the functional recovery after peripheral nerve injury., (Copyright © 2019 Elsevier B.V. and Japan Neuroscience Society. All rights reserved.)

Identification of modifier genes influencing phenotype of cystic fibrosis (CF) patients has become a challenge in CF pathophysiology, prognostic estimations and development of new therapeutic strategies. The aim of this study was to explore the association between four genetic polymorphisms of three modifier genes with CF, by comparing their alleles, genotypes and haplotype frequencies in patients and controls. In this favor, two regulatory polymorphic loci in TNFα promoter (-857C/T, rs1799724 and -238A/G, rs361525) and two functional polymorphic loci in TNFR1 (+36A/G, rs767455) and TNFR2 (+587T/G, rs1061622) were genotyped in 70 patients and 79 controls, using PCR-RFLP. Clinical pulmonary data were also recorded from all studied patients. Results indicated that an association was observed between both T allele and CT/TT genotypes of TNFα (P = 0.0005, OR = 7.06, 95% CI = 3.71-13.45) with CF under dominant model of inheritance. GG genotype of TNFR2 +587 (P = 0.0005, OR = 4.92, 95%CI = 2.34-10.34) was significantly associated with CF using recessive model. Consistently, more severe pulmonary disorder was found for patients carrying either T dominant allele of TNFα -857 or GG genotype of TNFR2 +587 polymorphic sites. Despite an association of A-T and G-T haplotypes with CF, no significant association was found between these haplotypes and clinical parameters of CF. Overall, TNFα -857 T allele and GG genotype of TNFR2 +587 were more frequent in CF patients compared to healthy controls and hence, they showed an association with CF and severe pulmonary phenotype in Iranian patients., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: Mononuclear phagocytes are thought to significantly contribute to cytokine regulation at the maternal-foetal interface, but the role of placental macrophages has been poorly investigated. TNFα and VEGF were demonstrated to have regulatory effects on basic structures of the placenta, particularly the trophoblast and blood vessels. The aims of this study were to determine the expression of TNFα, VEGF and related receptors in placental macrophages, and how does the participation of placental macrophages alter with gestational age in TNFα- and VEGF-mediated signaling., Methods: Macrophages were isolated from placental villous tissue from normal pregnancies at either 9-12 or 38-40 weeks gestation. Cell surface receptors (TNFR1, TNFR2, VEGFR1, and VEGFR2) and intracellular TNFα and VEGF were quantified by flow cytometry after antibody staining. Basal and stimulated secretion of both cytokines and soluble TNF receptors was quantified by cytometric bead arrays. Secreted VEGFR1 was measured by ELISA., Results: The expression of TNFR1 and VEGFR1 was remarkably variable and did not change from first to third trimester. There was minimal basal TNFα production in the placental macrophages, but nearly all cells in the population produced VEGF. TNFα and VEGF secretion increased with gestational age accompanied by decreased secretion of the antagonists sTNFR1 and sVEGFR. Macrophages isolated from early term placentas were less effective in responding to bacterial endotoxin. Lipopolysaccharide induced increases in the secretion of TNFα, TNFR1, TNFR2, and VEGFR1 but did not affect the production of VEGF. In late pregnancy, a significant correlation was observed between TNFR1 and VEGFR1., Discussion: The progression of pregnancy is accompanied by the concerted increase in TNFα and VEGF secretion and decrease in the production of their soluble receptors, but the expression of cell surface receptors does not depend on gestational age. The observed patterns of basal and stimulated expression of TNFα and VEGF may reflect the dual immune and morphogenetic roles of placental macrophages in gestation. Compatible patterns of TNFR1 and VEGFR1 expression suggest common regulatory pathways for these receptors., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Tumor necrosis factor-α (TNFα)-induced reactions are effective to maintain homeostasis; however, excessive responses play progressive roles in the pathogenesis of various chronic inflammatory diseases. We demonstrate that TNFα triggered the release of its receptor TNFR1 as a content of extracellular vesicles (EVs) from the human bronchial epithelial cell, BEAS-2b. The TNFR1 cytoplasmic domain binding partner, TNFR-associated death domain (TRADD), was released by TNFα treatment along with TNFR1. TNFα-triggered release of EVs was decreased in the presence of amitriptyline, an inhibitor of acid sphingomyelinase (A-SMase), or of GW4869, an inhibitor of neutral sphingomyelinase (N-SMase), indicating that EVs containing TNFR1 and TRADD are released through A-SMase and N-SMase dependent manners. From sucrose density gradient analysis, each sphingomyelinase is involved in the generation of distinct populations of EVs. Inhibition of A-SMase or N-SMase resulted in significantly increased responses to TNFα in parental cells. Given that TRADD serves as a platform for the assembly of subsequent signaling molecules, the TNFα triggered release of TNFR1 and TRADD might be an effective strategy for down regulation of the TNFα responses of parental cells., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Adenosine, a metabolite of ATP, ubiquitously exists in a wide range of organs and tissues. We previously reported that adenosine was implicated in apoptosis in many cancer cells by extrinsic and/or intrinsic pathways. Here, we found that adenosine suppresses the cell growth by induction of apoptosis of human colonic cancer cells through a novel mechanism. Adenosine suppresses the cell growth of human SW620 and SW480 colon cells in an adenosine transporter and adenosine kinase dependent manner. Moreover, the cell growth suppression is induced by apoptosis through activation of caspase-3 and PARP, and accumulation of ROS in cells. Importantly, we found that adenosine increases the expression of TNFR1 and RIPK1 and the phosphorylation of p38. Knockdown of TNFR1 or RIPK1 impairs the activation of p38, blocks the cleavage of PARP, and provides partially, yet significantly protection from cell death, including reducing the ROS generation in the colon cancer cells. These results indicate that a TNFR1/RIPK1/P38 axis is present in adenosine-induced apoptosis of colonic cancer cells. This axis triggers apoptosis and plays crucial roles in relay of the death signaling. Our study also provides additional experimental evidence for adenosine as a potent therapeutic drug in cancer therapy., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Patients suffering from neuropathic pain have a higher incidence of mood disorders such as depression. Increased expression of tumor necrosis factor (TNF) has been reported in neuropathic pain and depressive-like conditions and most of the pro-inflammatory effects of TNF are mediated by the TNF receptor 1 (TNFR1). Here we sought to investigate: (1) the occurrence of depressive-like behavior in chronic neuropathic pain and the associated forms of hippocampal plasticity, and (2) the involvement of TNFR1-mediated TNF signaling as a possible regulator of such events. Neuropathic pain was induced by chronic constriction injury of the sciatic nerve in wild-type and TNFR1(-/-) mice. Anhedonia, weight loss and physical state were measured as symptoms of depression. Hippocampal neurogenesis, neuroplasticity, myelin remodeling and TNF/TNFRs expression were analyzed by immunohistochemical analysis and western blot assay. We found that neuropathic pain resulted in the development of depressive symptoms in a time dependent manner and was associated with profound hippocampal alterations such as impaired neurogenesis, reduced expression of neuroplasticity markers and myelin proteins. The onset of depressive-like behavior also coincided with increased hippocampal levels of TNF, and decreased expression of TNF receptor 2 (TNFR2), which were all fully restored after mice spontaneously recovered from pain. Notably, TNFR1(-/-) mice did not develop depressive-like symptoms after injury, nor were there changes in hippocampal neurogenesis and plasticity. Our data show that neuropathic pain induces a cluster of depressive-like symptoms and profound hippocampal plasticity that are dependent on TNF signaling through TNFR1., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Inflammation can be either beneficial or detrimental to the liver, depending on multiple factors. Mild (i.e., limited in intensity and destined to resolve) inflammatory responses have indeed been shown to exert consistent hepatoprotective effects, contributing to tissue repair and promoting the re-establishment of homeostasis. Conversely, excessive (i.e., disproportionate in intensity and permanent) inflammation may induce a massive loss of hepatocytes and hence exacerbate the severity of various hepatic conditions, including ischemia-reperfusion injury, systemic metabolic alterations (e.g., obesity, diabetes, non-alcoholic fatty liver disorders), alcoholic hepatitis, intoxication by xenobiotics and infection, de facto being associated with irreversible liver damage, fibrosis, and carcinogenesis. Both liver-resident cells (e.g., Kupffer cells, hepatic stellate cells, sinusoidal endothelial cells) and cells that are recruited in response to injury (e.g., monocytes, macrophages, dendritic cells, natural killer cells) emit pro-inflammatory signals including - but not limited to - cytokines, chemokines, lipid messengers, and reactive oxygen species that contribute to the apoptotic or necrotic demise of hepatocytes. In turn, dying hepatocytes release damage-associated molecular patterns that-upon binding to evolutionary conserved pattern recognition receptors-activate cells of the innate immune system to further stimulate inflammatory responses, hence establishing a highly hepatotoxic feedforward cycle of inflammation and cell death. In this review, we discuss the cellular and molecular mechanisms that account for the most deleterious effect of hepatic inflammation at the cellular level, that is, the initiation of a massive cell death response among hepatocytes., (Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)