bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutathione peroxidase 8 negatively regulates caspase-4/11 to protect against colitis
Authors: Hsu Jye-Lin , Chen Tzu-Fan 
Published: January 2023

Abstract
Human caspase-4 and its mouse homolog caspase-11 are receptors for cytoplasmic lipopolysaccharide. Activation of the caspase-4/11-dependent NLRP3 inflammasome is required for innate defense and endotoxic shock, but how caspase-4/11 is modulated remains unclear. Here, we show that mice lacking the oxidative stress sensor glutathione peroxidase 8 (GPx8) are more susceptible to colitis and endotoxic shock, and exhibit reduced richness and diversity of the gut microbiome. C57BL/6 mice that underwent adoptive cell transfer of GPx8-deficient macrophages displayed a similar phenotype of enhanced colitis, indicating a critical role of GPx8 in macrophages. GPx8 bound covalently to caspase-4/11 via disulfide bonding between cysteine 79 of GPx8 and cysteine 118 of caspase-4, which restrained caspase-4/11 activation, while GPx8 deficiency led to caspase-4/11-induced inflammation during colitis and septic shock. Inhibition of caspase-4/11 activation with small molecules reduced the severity of colitis in GPx8-deficient mice. Notably, colonic tissue from patients with ulcerative colitis displayed low levels of Gpx8 and high caspase-4 expression. In conclusion, these results suggest that GPx8 protects against colitis by negatively regulating caspase-4/11 activity.
The adr-2 Mutant Strain of C. elegans and the Effect of Gold Nanoparticles on Life Span and Induction of Immune Responses
Authors: Meiner Kavan V , Elfert Amr , Cotlet Mircea , Idris Sally , Delaney Tetyana 
Published: January 2023

Abstract
Nanoparticles (NP) are widely used for domestic, industrial and medical applications. However, because of their nano-size they can easily penetrate cellular membranes, causing increased damage to the mitochondrial and genomic DNA. NPs also were reported to induce inflammation, cell apoptosis and oxidative stress.
In this research, the effect of gold NPs on growth, reproduction, fecundity, life span as well as induction of immune responses in Caenorhabditis elegans (C. elegans) are studied. The nematode has proven to be the best model to study effects difficult to explore in humans. The adr-2 mutant C. elegans is highly susceptible to environmental toxicity and offer sensitive bioassays to study the impacts of gold NPs on the worm. Two groups of adr-2 mutant C. elegans were grown. One group was exposed to gold NPs and the responses were analyzed and compared to the control group without nanoparticles. The two groups of C. elegans were observed over 2 months, thrashes were counted and the experiment was repeated several times. Findings showed that the thrash count for mutant strains decreases. Thus, at 0 minutes the thrash count was 55, reached 45 at two minutes, and decreased to 30 at four minutes. The other environmental contributors to this effect are under evaluation. The preliminary results showed that both groups had no visible changes. Nematodes were imaged using confocal differential interference contrast (DIC) microscopy. Several different pathways (p38 MAPK (PMK-1) and insulin like receptors (DAF-2)) could be activated to contribute to stress resistance to the NPs. Mutant strains of C. elegans for these receptors need to be tested to get a better understanding of the effect of the gold NPs on the immune responses.
Development of interferon-stimulated gene expression from embryogenesis through adulthood, with and without constitutive MDA5 pathway activation
Authors: Poeschla Eric M. , Bankers Laura 
Published: January 2023

Abstract
Pathogen-associated molecular patterns, e.g. dsRNA, activate expression of interferon-stimulated genes (ISGs), which protects hosts from infection. While transient ISG upregulation is essential for effective innate immunity, constitutive activation typically causes harmful autoimmunity in mice and humans, often including severe developmental abnormalities. We have shown that transgenic mice expressing a picornavirus RNA-dependent RNA polymerase outside the viral context (RdRP mice) exhibit lifelong, MDA5-dependent, and quantitatively dramatic upregulation of many ISGs, which confers broad viral infection resistance. Remarkably, RdRP mice never develop autoinflammation, interferonopathy, or any other discernible abnormalities. Here we used RNA-seq and other methods to analyze ISG expression across five time points from fetal development to adulthood in both wild-type and RdRP mice. In RdRP mice, the proportion of upregulated ISGs increased during development, with the most dramatic induction occurring two weeks postnatally. The immensely amplified ISG profile is then maintained lifelong. We further determined that blocking the type I interferon receptor reverses the amplified ISG transcriptome in adults. Molecular pathways and biological functions associated with innate immune signaling are only activated postnatally, suggesting dampened fetal responsiveness to innate immune stimuli. Similarly, functions supporting viral replication are only inhibited postnatally. In conclusion, the uniquely tolerated amplified ISG state of RdRP mice is mostly triggered early postnatally, is maintained through adulthood, and requires ongoing type I IFN signaling to maintain the augmented innate immune state.
Exercise-stimulated resolvin biosynthesis in adipose tissue is abrogated by obesity-induced adrenergic dysfunction
Authors: Hellmann Jason , Lynch William , Calderin Ernesto Pena , Sansbury Brian E. , Spite Matthew , Hill Bradford G. 
Published: January 2023

Abstract
Adipose tissue (AT) inflammation is associated with obesity-induced insulin resistance. Exercise (Exe) prevents the development of chronic inflammatory diseases and insulin resistance largely through unknown mechanisms. We provide data that specialized proresolving lipid mediators (SPM) contribute to the anti-inflammatory effect of Exe. Compared with sedentary controls (Sed), mice exposed to 4 wk of Exe showed elevated AT expression of SPM biosynthetic enzyme Alox15 (Sed 1.12±0.2 vs Exe 1.68±0.1 relative expression, n=5–7), SPM levels (Sed vs Exe; RvD1 156.7±12.0 vs 223.0±24.7; 17R-RvD1 354.0±35.9 vs 534.4±98.9; RvD4 31.31±6.9 vs 123.1±30.7; and 17R-RvD3 2.92±1.1 vs 8.20±1.7 pg/g, n=5–7), and M2 macrophages (F4/80+CD301+; Sed 17.5±3.2 vs Exe 40.9±4.5 %F4/80+, n=4–6). These changes were diet-dependent as high fat (HFD) abrogated this Exe effect in AT when compared with low fat (LFD) controls. The exercise-stimulated Alox15 expression was restricted to AT macrophages (F4/80+ cells; LFD Sed 0.11±0.03 vs LFD Exe 0.23±0.03; HFD Sed 0.10±0.04 vs HFD Exe 0.08±0.02 relative expression, n=3–6), as adipocytes isolated from Exe mice showed no difference compared with Sed controls. That epinephrine (Epi) is released with exercise and stimulates macrophage Alox15 expression and RvD1 production, we questioned if Epi biosynthesis is affected by HFD. HFD feeding diminished expression of phenylethanolamine N-methyltransferase compared with controls (LFD 1.0±0.25 vs HFD 0.36±0.15, n=4). Similarly, obese-diabetic mice (db/db) also showed reduced catecholamine production and biosynthetic enzyme levels. These results suggest that obesity-induced adrenergic dysfunction abrogates exercise-stimulated resolvin production in AT.
Mutations in the critical domain of human cathelicidin LL-37 affect neutralization of IAV
Authors: De Luna Xavier , White Mitchell , Hsieh I-Ni , Hartshorn Kevan L 
Published: January 2023

Abstract
Influenza A Virus (IAV) is the virus responsible for the flu and affects 3 to 5 million people around the world. Although vaccines exist for common strains of IAV, whenever pandemic strains of IAV arise humans are largely unprotected. Thus, new treatment strategies are required for pandemic strains of IAV as well as serious cases of IAV infection that can result in a bacterial superinfection. Treatments that reduce viral load in an infected host would be optimal to reduce virus spread as well as to potentially alleviate viral burden on the host. Mammals have many host defense peptides such defensins, lectins and cathelicidins. Cathelicidins are short cationic peptides that are antimicrobial in nature, and have been shown to have anti-IAV properties along with other antimicrobial functions. A critical domain of LL-37, the only human cathelicidin, has been shown to have a central helix with a hydrophobic surface. This critical domain is the minimum sequence of LL-37 required to have antimicrobial properties. There is no consensus on the mechanism LL-37 utilizes to neutralize bacteria and viruses. However, we hypothesize that by mutating single hydrophobic residues in the critical domain to a hydrophilic residue we can see changes in LL-37 neutralization of various IAV strains. Using fluorescent focus assays, we can quantify IAV titers after exposure to LL-37 and other cationic peptides. Here we show that reducing the hydrophobic residues within the critical domain of LL-37 reduces seasonal and pandemic IAV titers in vitro. These results lend credence to the theory of the hydrophobic surface of LL-37 is responsible for its anti-IAV effects.
Hyper-ISGylation promotes acute pulmonary pathology during chronic viral infection
Authors: Shaabani Namir , Zak Jaroslav , Teijaro John R 
Published: January 2023

Abstract
ISG15 is one of the strongest type I interferon (IFN-I) stimulated genes (ISGs) which is conjugated to proteins in an enzymatic process termed ISGylation. Protein ISGylation is subsequently reversed by the enzyme Usp18 which acts in a de-ubiqutinase fashion to remove SIG15 from target proteins. Many proteins are ISGylated following IFN-I signaling however, immunological studies have been limited to the anti-viral properties of ISG15 conjugation while its regulation of innate and adaptive immune responses has been poorly studied. Here using Usp18−/− and enzymatically inactive (Usp18C61A/C61A Knock-in) mouse models, we show that hyper-ISGylation during chronic viral infection leads to severe immune pathology characterized by hematological disruptions, cytokine amplification, lung vascular leakage and death. The pathology associated with chronic infection required T cells but not T cell-intrinsic Usp18 expression. We reveal that lack of Usp18 in LysM+ cells reproduced the pathological manifestations observed in Usp18−/− or Usp18C61A/C61A mice. Using single cell sequencing, we observed that hyper-ISGylation during chronic infection altered neutrophil maturation and promoted an inflammatory neutrophil lung infiltrate. Importantly, neutrophil depletion reversed morbidity and mortality in Usp18C61A/C61A mice. In summary, we reveal Usp18’s enzymatic function is crucial for regulating inflammatory neutrophil differentiation and preventing immune hyperactivation during chronic viral infection. Moreover, our results suggest that hyper-ISGylation may drive the inflammatory pathology observed in Usp18-null patients and indicate that regulation of ISG15 expression or conjugation could lessen disease.
CD28 Induces Autophagy in Plasma Cells to Enhance Mitochondrial Respiration and Survival
Authors: Peng Peng , Liu Wensheng , Utley Adam , Chavel Colin , Carlson Louise , Olejniczak Scott H , Lee Kelvin P 
Published: January 2023

Abstract
Durable humoral immunity relies on the persistence of long-lived plasma cells (LLPC) that continuously produce protective antibodies. The prototypical T cell costimulatory molecule CD28, that is also expressed on LLPC, is critical to their survival but the mechanisms involved remain unclear. We found CD28 activation enhances autophagy in LLPC/multiple myeloma as evidenced by increased level of autophagy marker LC3II, elevated autophagosome numbers and decreased level of autophagic cargo receptor P62. Inhibition of autophagy by 3MA or BafA abolished CD28’s pro-survival effects. Mechanistically, CD28 activation increased the protein level of ATG5, a critical autophagy regulator, even with translation blockade, but this was abrogated by proteasome inhibition. Knocking down atg5 eliminated CD28’s pro-survival effects, suggesting CD28 signaling regulates ATG5 degradation to sustain pro-survival autophagy. CD28 activation significantly increased mitochondrial respiration and blocking autophagy prevented this. Free fatty acids (FFA) can be degraded from cellular lipid droplets (LD) by lipophage, a selective form of autophagy, to fuel mitochondrial respiration. We found CD28 activation decreased LD staining and blocking autophagy prevented this. Blocking lipophagic lipase by lalistat eliminated CD28-induced oxidative phosphorylation and pro-survival effects. Addition of FFA (oleic and palmitic acids) boosted oxidative phosphorylation and restored survival with autophagy inhibition but not with fatty acid oxidation blockade. These data suggest CD28 signaling regulates ATG5 protein degradation to enhance autophagy and this in return produces FFA to sustain mitochondrial respiration and support LLPC survival.
Friend or foe? A systematic evaluation of NKT and NK cells as prognostic markers in colorectal carcinoma
Authors: Feng Hao , Tong Huan , Thasler Wolfgang , Xia Qiang 
Published: January 2023

Abstract

BACKGROUND
Natural killer t(NKT) cells and Natural killer (NK) cells orchestrate immune responses in tumor progression. NKT and NK cells have been suggested as prognostic markers for cancer patients. However, the results were controversial. In the present study, we present a systematic review and meta-analysis of studies assessing the prognostic value of NKT and NK cells in colorectal cancers, respectively.

METHODS
We performed a systematic literature search and included studies using immunofluorescence or flow cytometry and survival analysis to assess the prognostic value of NKT and NK cells in colorectal cancer. We performed a meta-analysis of studies providing necessary statistical data and investigated prognostic value of NKT and NK cells.

RESULTS
Of the 275 articles identified, 169 were eligible for this systematic review, and eight were included in the meta-analysis. Both NKT and NK cells were the most promising predictors of disease-free survival (DFS) and overall survival (OS) in colorectal cancer patients. Both NKT-high and NK-high were positively correlated to better OS, respectively (NKT: p=0.002, HR 2.91, 95%CI 1.46~5.80; NK: p&lt;0.0001, HR 3.87, 95%CI 1.97–7.62). Intriguingly, NK-high was also associated with better DFS (NK: p&lt;0.0001, HR 3.42, 95%CI 2.05–5.69); however, NKT-high presented the opposite trend for DFS(NKT: p&lt;0.0001, HR 5.28, 95%CI 2.35–11.84).

CONCLUSION
Proper reporting of the association between NKT/NK allows the reader to evaluate the quality and reliability of the previously reported data. The promising results might boost the interest in tumor immunology such as CAR-NK and CAR-NKT. The prognostic value of NKT and NK cells should be validated in large, standardized studies.
Novel role for gelatinases in modulating metabolic reprogramming associated with T cell receptor stimulation in CD4+ T cell
Authors: Onwuha-Ekpete Lillian , Tokmina-Roszyk Dorota , Fields Gregg 
Published: January 2023

Abstract
The gelatinases, MMP-2 and MMP-9, are proteolytic enzymes with diverse physiological roles. They are linked with various aspects of the immune response, such as leukocyte trafficking and cytokine activation. However, their dysregulation is associated with various pathologies such as metastasis in cancer progression and blood-brain barrier disruption in multiple sclerosis. Much of what is known about the gelatinases is in context of their extracellular activities. However, recent studies including this study suggest an intracellular role in immune cell activation.
Our findings suggest, that gelatinase activity can modulate T cell bioenergetics, affecting both oxidative phosphorylation and the glycolytic pathways with a greater influence on the latter. This results in a mitigated CD4+ T cell response to TCR stimulation. Upon stimulation, CD4+ T cells lacking gelatinase activity, demonstrate a reduced capacity to be activated as determined by the expression of early activation markers, proliferation, and the production of effector cytokines. In addition, RNA-seq analysis of control and gelatinase inhibited CD4+ T cells highlight key proteins associated with both the immune system and metabolic processes as predicted by STRING. We confirm our pharmacological studies with the genetic ablation of the gelatinases and further analysis of these shRNA treated T cells using the Nanostring metabolic panel. In addition, we demonstrate in-vivo relevancy using a murine model for multiple sclerosis known to be initiated by CD4+ T cells; gelatinase inhibition resulted in reduced clinical severity. These results suggest an intracellular role for gelatinases in CD4+ T cell mediated diseases and their potential as therapeutic targets.
Perinatal androgen exposure impacts mast cell development and mediator storage
Authors: Bali Vedrana , Mackey Emily , Moeser Adam 
Published: January 2023

Abstract
Mast cell (MC)-associated diseases often exhibit a female sex bias in both prepubertal children and adults. We have shown that female MCs store and release greater amounts of histamine which correlates with heightened anaphylaxis in both prepubertal and adult mice. Further, perinatal androgen exposure, a major organizing event in sex biology, reduced MC histamine storage and release, and the severity of anaphylaxis in prepubertal and adult female mice, thus demonstrating that perinatal androgens are critical early life drivers of MC sex differences, but the mechanisms remain poorly understood. The objective of this study was to determine how perinatal androgens impact MC development. RNA sequencing analysis of BMMCs derived from adult female and male mice that were previously exposed to perinatal androgens revealed significant down-regulation of a number of genes related to granule biogenesis and mediator storage of which included lactotransferrin (by −2.6 fold), proteoglycan 2 (by −3.9 fold), lipocalin 2 (by −1.4-fold), elastase (by −2.5 fold) and myeloperoxidase (by 1.4 fold). Current studies aim to confirm RNA seq data with qPCR and protein expression analysis and to define the critical period of androgen programming on MC development and function. Understanding the mechanisms by which early life androgens drive sex differences in MCs will be critical in understanding the origins of sex differences in MC and its role in health and disease.
Each feature of Th plasticity is regulated individually, balancing pathology and protection in malaria
Authors: Stephens Robin , Aussenac Florentin , Clark Lucinda Puebla , Wilson Kyle D. , Dent Alexander L. , Carpio Victor H. 
Published: January 2023

Abstract
Hybrid Th1/Tfh cells (IFN-γ+IL-21+CXCR5+) predominate in response to persistent infections. However, it is not clear if the function of these cells is plastic and might be modulated. In infection with Plasmodium spp, an IFN-γ+ T helper-1 (Th1) response controls initial parasitemia, while antibody and IL-21+CXCR5+ T follicular helper (Tfh) function effect final clearance. Supporting plasticity, we found that CD4-intrinsic Bcl6, Blimp-1 and STAT3 all regulate T-bet expression, which controls IFN-γ expression. While Bcl6 and Blimp-1 regulate the level of CXCR5, only T-bet, IL-27Rα and STAT3 strongly affected the cytokine bias of the Th1/Tfh phenotype. Infected mice with STAT3-deficient T cells produced less antibody, and more Th1-like IFN-γ+IL-21−CXCR5lo T cells, significantly increasing protection from re-infection. Conversely, reduced Th1 bias in re-infected T-bet KO was reflected in prolonged secondary parasitemia. Signs of pathology were somewhat prolonged in Th1-biased animals supporting an evolutionary tradeoff between control of parasite and tissue damage. In summary, each feature of hybrid Th1/Tfh population in Plasmodium infection is uniquely regulated and the cytokine bias of memory T cells can be modified to enhance the effectiveness of the response.
IkZF and STAT factor regulatory modules as drivers of TH1 and TFH cell differentiation decisions
Authors: Jones Devin M , Read Kaitlin A , Sreekumar Bharath , Powell Michael Duane , Warren Robert T , Oestreich Kenneth J 
Published: January 2023

Abstract
CD4+ T helper cells are capable of differentiating into subsets that regulate distinct aspects of the immune response. The differentiation of these populations is driven by subset-specific cytokine signals and downstream transcription factor networks that are responsible for promoting the unique gene expression programs of each cell type. It is well-established that cytokine signals are propagated by Signal Transducer and Activator of Transcription (STAT) factors. Recently, we demonstrated that STAT3 and Aiolos, a member of the Ikaros Zinc Finger (IkZF) family, form a novel transcriptional complex that directly induces expression of the T follicular helper (TFH) cell lineage defining factor, Bcl-6. Interestingly, we have also found that a second IkZF factor Eos interacts with STAT5 and forms an opposing complex in T helper 1 (TH1) cells that promotes expression of the Bcl-6 antagonist, Blimp-1. However, whether additional IkZF/STAT complexes function downstream of other cytokine signals in these cell populations is unclear. Here, we report that in vitro-generated TH1 and TFH1-like cells similarly express Ikaros concurrent with increased STAT4 activation downstream of IL-12 signaling. Using co-immunoprecipitation analyses, we were also able to detect interactions between Ikaros and STAT4. Furthermore, as with the other IkZF/STAT complexes, we find that interactions between Ikaros and STAT4 were dependent upon the IkZF C-terminal ZF domain, suggesting that this is a conserved regulatory feature of IkZF/STAT complex formation. Current efforts are now aimed at identifying whether mechanistic interplay between the Ikaros/STAT4 complex and the other IkZF/STAT factors may ultimately dictate TH1 or TFH cell fate and function.
Protective function of DUSP4 in DSS-induced colitis
Authors: Lu Yi , Zhang Yongliang 
Published: January 2023

Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic inflammation of the gastrointestinal tract. The mitogen-activated protein kinase (MAPK) signalling, an evolutionary conserved cell signalling pathway, is associated with IBD. MAPKs comprises ERK, P38, and JNK, which are activated by upstream MKKs and MKKKs, and are inactivated by dual specificity phosphatases (DUSPs). DUSP4 (MPK2) is a member of DUSP protein family and was found to be involved in various physiological processes. However the role of DUSP4 in IBD is yet to be examined. In this study, we utilized DSS-induced colitis mouse model to investigate the function of DUSP4 in this disease. We found that DUSP4 knockout (KO) mice were more susceptible to DSS-induced colitis, which was demonstrated by more weight loss and higher histological score than wild-type (WT) mice. Consistently, expression of inflammatory cytokines, including IL-6, TNF-α, IL-17A, and CXCL-1, was enhanced in both proximal and distal colon of DUSP4 KO mice compared to WT mice. Moreover, excessive CD8+ and CD4+ cells, especially IL-17A-expressing CD4+ T cells, were identified in the mesenteric lymph node (mLN) of the KO mice. Together, these results demonstrated that deficiency of DUSP4 resulted in increased inflammation in the gut in response to DSS.