Neuroimmune Consequences of eIF4E Phosphorylation on Chemotherapy-Induced Peripheral Neuropathy

Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting side effect that occurs in up to 63% of patients and has no known effective treatment. A majority of studies do not effectively assess sex differences in the onset and persistence of CIPN. Here we investigated the onset of CIPN, a point of therapeutic intervention where we may limit, or even prevent the development of CIPN. We hypothesized that cap-dependent translation mechanisms are important in early CIPN development and the bi-directional crosstalk between immune cells and nociceptors plays a complementary role to CIPN establishment and sex differences observed. In this study, we used wild type and eIF4E-mutant mice of both sexes to investigate the role of cap-dependent translation and the contribution of immune cells and nociceptors in the periphery and glia in the spinal cord during paclitaxel-induced peripheral neuropathy. We found that systemically administered paclitaxel induces pain-like behaviors in both sexes, increases helper T-lymphocytes, downregulates cytotoxic T-lymphocytes, and increases mitochondrial dysfunction in dorsal root ganglia neurons; all of which is eIF4E-dependent in both sexes. We identified a robust paclitaxel-induced, eIF4E-dependent increase in spinal astrocyte immunoreactivity in males, but not females. Taken together, our data reveals that cap-dependent translation may be a key pathway that presents relevant therapeutic targets during the early phase of CIPN. By targeting the eIF4E complex, we may reduce or reverse the negative effects associated with chemotherapeutic treatments.

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PD-L1 Inhibitors for the Treatment of Prostate Cancer

Current Drug Targets ◽

10.2174/1389450121666200609142219 ◽

2020 ◽

Vol 21 (15) ◽

pp. 1558-1565

Author(s):

Matteo Santoni ◽

Francesco Massari ◽

Liang Cheng ◽

Alessia Cimadamore ◽

Marina Scarpelli ◽

...

Keyword(s):

Prostate Cancer ◽

Clinical Trials ◽

T Lymphocytes ◽

Chronic Inflammation ◽

Immune Cells ◽

Response To Therapy ◽

Complex Series

The carcinogenesis of prostate cancer (PCa) results from a complex series of events. Chronic inflammation and infections are crucial in this context. Infiltrating M2 type macrophages, as well as neutrophils and T lymphocytes, contribute to PCa development, progression and response to therapy. The preliminary findings on the efficacy of immunotherapy in patients with PCa were not encouraging. However, a series of studies investigating anti-PD-L1 agents such as Atezolizumab, Avelumab and Durvalumab used alone or in combination with other immunotherapies, chemotherapy or locoregional approaches are in course in this tumor. In this review, we illustrate the role of immune cells and PD-L1 expression during PCa carcinogenesis and progression, with a focus on ongoing clinical trials on anti-PD-L1 agents in this context.

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The role of miR-146a in dorsal root ganglia neurons of experimental diabetic peripheral neuropathy

Neuroscience ◽

10.1016/j.neuroscience.2013.11.057 ◽

2014 ◽

Vol 259 ◽

pp. 155-163 ◽

Cited By ~ 46

Author(s):

L. Wang ◽

M. Chopp ◽

A. Szalad ◽

Y. Zhang ◽

X. Wang ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Dorsal Root Ganglia ◽

Diabetic Peripheral Neuropathy ◽

Dorsal Root ◽

Dorsal Root Ganglia Neurons

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Susceptibility to Entamoeba histolytica intestinal infection is related to reduction in natural killer T-lymphocytes in C57BL/6 mice

Infectious Disease Reports ◽

10.4081/idr.2012.e27 ◽

2012 ◽

Vol 4 (1) ◽

pp. 27 ◽

Cited By ~ 3

Author(s):

Fabrício M.S. Oliveira ◽

Bernardo C. Horta ◽

Luana O. Prata ◽

Andrezza F. Santiago ◽

Andréa C. Alves ◽

...

Keyword(s):

T Lymphocytes ◽

Natural Killer ◽

Entamoeba Histolytica ◽

Protective Role ◽

Amoebic Liver Abscess ◽

Wild Type ◽

Quantitative Analyses ◽

Cd1 Mice ◽

Natural Killer T

Entamoeba histolytica is a protozoan that causes amoebiasis. Recent studies demonstrated that natural killer T lymphocytes (NKT) are critical for preventing the development of amoebic liver abscess. In spite of that, there are only a handful of studies in the area. Herein, we explored the role of NKT cells in E. histolytica infection using C57BL/6 wild-type and CD1-/- mice. Animals were inoculated with E. histolytica and sacrificed 48 hours later to collect caecum samples that were used for quantitative analyses of lesions, trophozoites, NK1.1+ T lymphocytes and expression of the mucus protein MUC-2 by immunohistochemistry technique. Quantitative analyses confirmed that the frequency of NK1.1+ T cells was significantly lower in samples from C57BL/6 CD1-/- mice as compared to their wild type (WT) counterparts. The extension of necrotic mucosa was larger and the number of trophozoites higher in Entamoeba (Eh)-infected CD1-/- mice when compared with Eh-infected WT mice. In mice from both groups, noninfected (CTRL) and Eh-infected CD1-/-, there was a reduction in the thickness of the caecal mucosa and in the MUC-2-stained area in comparison with CTRL- and Eh-WT mice. Our results showed that NKT lymphocytes contribute to resistance against Entamoeba histolytica infection and to the control of inflammation in the colitis induced by infection. The presence of a normal epithelial layer containing appropriate levels of mucus had also a protective role against infection.

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Indoleamine 2,3-Dioxygenase 2 Deficiency Exacerbates Imiquimod-Induced Psoriasis-Like Skin Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms21155515 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5515

Author(s):

Kento Fujii ◽

Yasuko Yamamoto ◽

Yoko Mizutani ◽

Kuniaki Saito ◽

Mariko Seishima

Keyword(s):

Immune Responses ◽

Immune Cells ◽

Skin Inflammation ◽

Kynurenine Pathway ◽

Immune Functions ◽

Wild Type ◽

Indoleamine 2,3 Dioxygenase ◽

Tnf Α ◽

In The Wild

Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme known to suppress immune responses, and several reports have showed that it is associated with psoriasis. IDO2 is an isoform of IDO1, recently identified as a catalytic enzyme in the tryptophan-kynurenine pathway, which is expressed in dendritic cells and monocytes. The expression of IDO2 in immune cells suggests that IDO2 may contribute to immune functions. However, the role of IDO2 in the pathogenesis of psoriasis remains unclear. In this study, to elucidate the role of IDO2 in psoriasis, we assessed imiquimod (IMQ)-induced psoriasis-like dermatitis in IDO2 knockout (KO) mice. Skin inflammation, evaluated by scoring erythema, scaling, and ear thickness, was significantly worse in the IDO2 KO mice than in the wild-type (WT) mice. The mRNA expression levels of TNF-α, IL-23p19, and IL-17A, key cytokines involved in the development of psoriasis, were also increased in the IDO2 KO mice. Furthermore, immunohistochemistry revealed that the number of Ki67-positive cells in the epidermis and CD4-, CD8-, and IL-17-positive lymphocytes infiltrating the dermis were significantly increased in the IDO2 KO mice. These results suggest that IDO2 might decrease IL-17 expression, thereby resulting in the suppression of skin inflammation in IMQ-induced psoriasis-like dermatitis.

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Sex differences in stroke across the lifespan: The role of T lymphocytes

Neurochemistry International ◽

10.1016/j.neuint.2017.01.009 ◽

2017 ◽

Vol 107 ◽

pp. 127-137 ◽

Cited By ~ 9

Author(s):

Javiera Bravo-Alegria ◽

Louise D. McCullough ◽

Fudong Liu

Keyword(s):

Sex Differences ◽

T Lymphocytes

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Cytoplasmic Copper Detoxification in Salmonella Can Contribute to SodC Metalation but Is Dispensable during Systemic Infection

Journal of Bacteriology ◽

10.1128/jb.00437-17 ◽

2017 ◽

Vol 199 (24) ◽

Cited By ~ 8

Author(s):

Luke A. Fenlon ◽

James M. Slauch

Keyword(s):

Superoxide Dismutase ◽

Immune Cells ◽

Gastrointestinal Disease ◽

Systemic Infection ◽

Copper Binding ◽

Wild Type ◽

Triple Mutant ◽

Content Type

ABSTRACT Salmonella enterica serovar Typhimurium is a leading cause of foodborne disease worldwide. Severe infections result from the ability of S. Typhimurium to survive within host immune cells, despite being exposed to various host antimicrobial factors. SodCI, a copper-zinc-cofactored superoxide dismutase, is required to defend against phagocytic superoxide. SodCII, an additional periplasmic superoxide dismutase, although produced during infection, does not function in the host. Previous studies suggested that CueP, a periplasmic copper binding protein, facilitates acquisition of copper by SodCII. CopA and GolT, both inner membrane ATPases that pump copper from the cytoplasm to the periplasm, are a source of copper for CueP. Using in vitro SOD assays, we found that SodCI can also utilize CueP to acquire copper. However, both SodCI and SodCII have a significant fraction of activity independent of CueP and cytoplasmic copper export. We utilized a series of mouse competition assays to address the in vivo role of CueP-mediated SodC activation. A copA golT cueP triple mutant was equally as competitive as the wild type, suggesting that sufficient SodCI is active to defend against phagocytic superoxide independent of CueP and cytoplasmic copper export. We also confirmed that a strain containing a modified SodCII, which is capable of complementing a sodCI deletion, was fully virulent in a copA golT cueP background competed against the wild type. These competitions also address the potential impact of cytoplasmic copper toxicity within the phagosome. Our data suggest that Salmonella does not encounter inhibitory concentrations of copper during systemic infection. IMPORTANCE Salmonella is a leading cause of gastrointestinal disease worldwide. In severe cases, Salmonella can cause life-threatening systemic infections, particularly in very young children, the elderly, or people who are immunocompromised. To cause disease, Salmonella must survive the hostile environment inside host immune cells, a location in which most bacteria are killed. Our work examines how one particular metal, copper, is acquired by Salmonella to activate a protein important for survival within immune cells. At high levels, copper itself can inhibit Salmonella. Using a strain of Salmonella that cannot detoxify intracellular copper, we also addressed the in vivo role of copper as an antimicrobial agent.

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Sex Differences in Otolaryngology: Focus on the Emerging Role of Estrogens in Inflammatory and Pro-Resolving Responses

International Journal of Molecular Sciences ◽

10.3390/ijms22168768 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8768

Author(s):

Sheng-Dean Luo ◽

Tai-Jan Chiu ◽

Wei-Chih Chen ◽

Ching-Shuen Wang

Keyword(s):

Sex Differences ◽

Sex Hormones ◽

Immune Cells ◽

Vocal Fold ◽

Hormone Receptors ◽

Inflammatory Responses ◽

Proinflammatory Responses ◽

Males And Females ◽

Nose And Throat

Otolaryngology (also known as ear, nose, and throat (ENT)) diseases can be significantly affected by the level of sex hormones, which indicates that sex differences affect the manifestation, pathophysiology, and outcomes of these diseases. Recently, increasing evidence has suggested that proinflammatory responses in ENT diseases are linked to the level of sex hormones. The sex hormone receptors are present on a wide variety of immune cells; therefore, it is evident that they play crucial roles in regulating the immune system and hence affect the disease progression of ENT diseases. In this review, we focus on how sex hormones, particularly estrogens, regulate ENT diseases, such as chronic rhinosinusitis, vocal fold polyps, thyroid cancer, Sjögren’s syndrome, and head and neck cancers, from the perspectives of inflammatory responses and specialized proresolving mediator-driven resolution. This paper aims to clarify why considering sex differences in the field of basic and medical research on otolaryngology is a key component to successful therapy for both males and females in the future.

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Role of sigma 1 receptor in high fat diet-induced peripheral neuropathy

Biological Chemistry ◽

10.1515/hsz-2017-0117 ◽

2017 ◽

Vol 398 (10) ◽

pp. 1141-1149 ◽

Cited By ~ 2

Author(s):

Tieying Song ◽

Jianhui Zhao ◽

Xiaojing Ma ◽

Zaiwang Zhang ◽

Bo Jiang ◽

...

Keyword(s):

Spinal Cord ◽

Peripheral Neuropathy ◽

High Fat Diet ◽

Tactile Allodynia ◽

Wild Type ◽

High Fat ◽

Sigma 1 Receptor ◽

Sigma 1 ◽

Nmdar Subunits

Abstract The neurobiological mechanisms of obesity-induced peripheral neuropathy are poorly understood. We evaluated the role of Sigma-1 receptor (Sig-1R) and NMDA receptor (NMDARs) in the spinal cord in peripheral neuropathy using an animal model of high fat diet-induced diabetes. We examined the expression of Sig-1R and NMDAR subunits GluN2A and GluN2B along with postsynaptic density protein 95 (PSD-95) in the spinal cord after 24-week HFD treatment in both wild-type and Sig-1R−/− mice. Finally, we examined the effects of repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice on peripheral neuropathy. Wild-type mice developed tactile allodynia and thermal hypoalgesia after 24-week HFD treatment. HFD-induced peripheral neuropathy correlated with increased expression of GluN2A and GluN2B subunits of NMDARs, PDS-95, and Sig-1R, as well as increased Sig-1R-NMDAR interaction in the spinal cord. In contrast, Sig-1R−/− mice did not develop thermal hypoalgesia or tactile allodynia after 24-week HFD treatment, and the levels of GluN2A, GluN2B, and PSD-95 were not altered in the spinal cord of HFD-fed Sig-1R−/− mice. Finally, repeated intrathecal administrations of selective Sig-1R antagonists BD1047 in HFD-fed wild-type mice attenuated peripheral neuropathy. Our results suggest that obesity-associated peripheral neuropathy may involve Sig-1R-mediated enhancement of NMDAR expression in the spinal cord.

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Murine T Lymphocytes Incapable of Producing Macrophage Inhibitory Protein-1 Are Impaired in Causing Graft-Versus-Host Disease Across a Class I But Not Class II Major Histocompatibility Complex Barrier

Blood ◽

10.1182/blood.v93.1.43 ◽

1999 ◽

Vol 93 (1) ◽

pp. 43-50 ◽

Cited By ~ 29

Author(s):

Jonathan S. Serody ◽

Donald N. Cook ◽

Suzanne L. Kirby ◽

Elizabeth Reap ◽

Thomas C. Shea ◽

...

Keyword(s):

T Cell ◽

T Lymphocytes ◽

Graft Versus Host Disease ◽

Class Ii ◽

Class I ◽

Wild Type ◽

Inhibitory Protein ◽

Host Disease ◽

Graft Versus Host

Abstract The routine use of bone marrow transplantation is limited by the occurrence of acute and chronic graft-versus-host disease (GVHD). Current approaches to decreasing the occurrence of GVHD after allogeneic transplantation use T-cell depletion, use immunosuppressive agents, or block costimulatory molecule function. The role of proteins in the recruitment of alloreactive lymphocytes has not been well characterized. Chemokines are a large family of proteins that mediate recruitment of mononuclear cells in vitro and in vivo. To investigate the role of T-cell production of the chemokine macrophage inhibitory protein-1 (MIP-1) in the occurrence of GVHD, splenocytes either from wild-type or from MIP-1−/− mice were administered to class I (B6.C-H2bm1) and class II disparate mice (B6-C-H2bm12). The incidence and severity of GVHD was markedly reduced in bm1 mice receiving splenocytes from MIP-1−/− mice as compared with mice receiving wild-type splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had significantly less weight loss and markedly reduced inflammatory responses in the lung and liver than mice receiving C57BL/6 splenocytes. Bm1 mice receiving MIP-1−/− splenocytes had a markedly decreased production of antichromatin autoantibodies and impaired generation of bm1-specific T lymphocytes versus wild-type mice. However, MIP-1−/− splenocytes easily induced GVHD when administered to bm12 mice. This data show that blockade of chemokine production or function may provide a new approach to the prevention or treatment of GVHD but that chemokines that recruit both CD4+ and CD8+ lymphocytes may need to be targeted.

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