bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunoparalysis is mediated by a dysfunctional IL-10/IL-12 axis in severe burn injury
Authors: Stepp Wesley H , Malfitano Madison , Long Clayton , Maile Robert , Cairns Bruce A 
Published: January 2023

Abstract
In the past year alone, burn injuries accounted for greater than 500,000 medical encounters in the United States. Few molecular markers exist that can detail the extent of burn severity or predict outcomes in burn patients. The identification of biomarkers that can accurately predict patients who are at a higher risk for in-hospital complications and would improve patient outcomes. In this study, we identified means to objectively quantify the degree of a patient’s burn injury and developed a gene-expression profile that identifies the degree of immune compromise in patients following significant burn trauma.
In a prospectively collected cohort of 54 burn patients, we identified that the amount of cell-free DNA in a patient’s plasma significantly correlates with the degree of burn severity (as determined by % total body surface area affected, %TBSA) (R2=0.4256; p&lt;0.0001) and length of hospital stay (R2=0.1895; p=0.0018). Using these data, we stratified patients into either low-moderate injury (&lt;15% TBSA) or severe injury (&gt;15% TBSA) for gene expression analysis of key immunoregulatory molecules. When compared to uninjured, healthy control subjects (N=13), patients with low-moderate injuries (N=33) had 10-fold upregulation in IL-10 expression (p=0.0004), while patients with severe burn injuries (N=18) had a more pronounced upregulation in IL-10 gene expression (25.85-fold increase, p=0.0029). Conversely, IL-12 gene expression remained constant in low-moderate burn patients but was significantly decreased in patients with severe burn injuries. These data suggest that severe burn injury generates a profoundly dysfunctional immune response that may prove a significant challenge to recovery.
Elevated expression of TLR10 in the adipose tissue in obesity: Implication in metabolic inflammation
Authors: THOMAS REEBY SARA , Kochumon Shihab , Sindhu Sardar , Ahmad Rasheed 
Published: January 2023

Abstract
Obesity is marked with larger adipocytes and increasing number of infiltrating immune cells within adipose tissue. These infiltrated immune cells are considered to be involved in the production of inflammatory mediators which cause chronic low grade inflammation called metabolic inflammation (MI). MI plays a key role in the development of insulin resistance (IR) and type-2 diabetes (T2D). Research has shown that the innate immune toll-like receptors (TLRs) specifically TLR2/TLR4 are involved in MI/IR. TLR10 is identified as a pattern recognition receptor without known ligand specificity or biological function and is highly expressed in tissue rich in immune cells. Recent studies have shown that TLR10 has been involved in innate immune responses against infections. However, its role in obesity/T2D remains to be elucidated. Therefore, we investigated the changes in the TLR10 expression and analyzed their association with inflammatory markers in the subcutaneous adipose tissues (AT) obtained from adults with/without T2D classified as lean, overweight, and obese based on BMI. Our data show upregulation of TLR10 expression (P&lt;0.05) in obese as compared with lean/overweight individuals and these changes correlated with BMI (P=0.0008) and body fat percentage (P=0.002). Increased TLR10 expression also correlated positively with various inflammatory signatures including TNF-α (r=0.71), CXCL10 (r=0.79), IL-23 (r=0.6), CCL5 (r=0.69), CCR5 (r=0.79); CCR2 (r= 0.95), IL-12A (r=0.73) and TLR2 (r=0.74). In T2D, TLR10 correlated only with BMI (P=0.001) and CCL5 (P=0.01). Collectively, our data show that increased AT-TLR10 expression is associated with signature inflammatory markers which may have significance in MI.
Molecular determinants of noncanonical inflammasome activation by LPS
Authors: Behl Bharat , Vanaja Sivapriya Kailasan , Rathinam Vijay 
Published: January 2023

Abstract
Septic shock is the leading cause of morbidity and mortality in intensive care units worldwide. Gram-negative bacteria constitute one of the most common causes of sepsis that results in high fatality by initiating an excessive and uncontrolled host inflammatory response. At the epicenter of this response is the innate immune detection of lipopolysaccharides (LPS). In addition to TLR4 recognition of LPS, recent studies revealed a new LPS sensing mechanism in the cytosol. Inflammatory caspases, such as caspase-11, detect LPS to execute pyroptosis, an inflammatory form of cell death, and caspase-1 activation. A prerequisite for the activation of noncanonical inflammasome is the transcriptional induction of caspase-11, which is mediated by TLR4-TRIF, type I interferon, and complement signaling. Additionally, guanylate binding proteins (GBPs), interferon regulatory factor 1, and IRGB10 orchestrate the release of LPS from the vacuolar bacterial pathogens into the cytosol. While the host factors involved in LPS activation of caspase-11 are fairly characterized, the role of bacterial factors in this process is not clear. Our new findings from this study delineate the bacterial components necessary for the optimal engagement of the cytosolic LPS sensing pathway and eliciting noncanonical inflammasome responses.
Lamina propria lymphocytes in sanroque mice produce proinflammatory cytokines that drive chronic small intestinal inflammation
Authors: Klein John R , Williams Alexander , Vigneswaran Nadarajah , Montufar-Solis Dina 
Published: January 2023

Abstract
Roquin is an E3 ligase that regulates mRNA stability. Mice with a mutation in the Rc3h1 gene and Roquin protein, referred to as Roquinsan/san or sanroque mice, develop extensive chronic inflammation and autoimmune pathologies. Our laboratory recently reported that beginning at 8 weeks of age sanroque mice also develop inflammation that is localized to the small intestine but is rare in the colon. Here, we demonstrate that small intestinal intraepithelial lymphocytes (IELs) are present in the epithelium of sanroque mice, but that cell recoverability is low using standard extraction techniques even though lamina propria lymphocytes (LPLs) can be recovered in normal numbers. In characterizing T cell costimulatory markers and activation molecules on LPLs in sanroque mice, we identified Ly6C and 4-1BB (CD137) as being expressed at elevated levels on small intestinal LPLs, and we show that both subsets, in conjunction with cells expressing the KLRG1 T cell activation molecule, are sources of the IL-17A, IFN-γ, and TNFα proinflammatory cytokines. TNFα was primarily produced by 4-1BB+, KLRG1− cells, but was also made by some 4-1BB−, KLRG1− cells, and 4-1BB−, KLRG1+ cells. These findings collectively suggest that the small intestinal inflammatory response in sanroque mice is driven, at least in part, by LPL activation through Ly6C, 4-1BB, and KLRG1 signaling, and they provide further evidence demonstrating the utility of using the sanroque mouse as an animal model of chronic inflammation in the small intestine.
Gut microbiota fermentation and inflammasome responses determine the effects of dietary fiber on intestinal inflammation
Authors: Singh Vishal , Saha Piu , Yeoh Beng San , Walker Rachel , Cai Jingwei , Xiao Xia , Shearer Gregory C. , Patterson Andrew D , Vijay-Kumar Matam 
Published: January 2023

Abstract
Short-chain fatty acids (SCFAs), major microbial fermentation products of dietary fiber in the gut, are shown to improve gut health. We hypothesized that soluble fiber (inulin and pectin) which are more accessible for microbiota fermentation may offer more pronounced mucoprotection than insoluble fiber (cellulose) in a murine model of chronic colitis. WT (BL6) mice receiving dietary cellulose exhibited robust colitis upon IL-10R neutralization as examined by serological, biochemical, histological and immunological parameters. Similar results were observed in colitis-prone toll-like receptor 5 knockout (Tlr5KO) mice. Surprisingly, prebiotic fiber inulin failed to protect against colitis in both WT and Tlr5KO mice. Remarkably, pectin ameliorates colitis development. GC-MS analysis of cecal content revealed that cecal butyrate, an inflammasome (NLRP3) response modulator in the gut, was augmented in inulin-fed colitic mice. Serum cytokine analysis showed that dietary inulin elevated IL-18, but diminished the IL-1 receptor antagonist (sIL-1Ra). On the flip side, dietary pectin reduced IL-18 and augmented sIL-1Ra. More importantly, suppressing butyrate production by metronidazole, which specifically depletes the butyrate producers in the gut, protected the mice from chronic colitis, suggesting that SCFAs-inflammasome axis shapes the beneficial effects of dietary fiber on the gut health. Collectively, mitigation of chronic colitis by dietary pectin can be partly explained by reduced cecal butyrate and elevated IL-1β inhibitor, sIL-1Ra. A detailed mechanistic study on how pectin-derived metabolites modulate inflammasome signaling may yield development of novel therapeutics to treat intestinal inflammation.
CCR2 promotes intestinal tumorigenesis through enhancing inflammation via IL-17 and IL-23 pathway
Authors: Jala Venkatakrishna R , Bodduluri Sobha Rani , Chilton Paula , Chheda Zinal S , Sharma Rajesh K , Singh Rajbir , Fleming Christopher Jay , Yan Jun , Bodduluri Haribabu 
Published: January 2023

Abstract
Chemokines and their receptors have been implicated in several cancers and metastasis including colon cancer. CCL2, a classic chemokine mediates biological functions via CCR2 receptor. In this study, we investigated the role of CCR2 in progression of intestinal tumors using spontaneous intestinal tumorigenesis mouse model, ApcMin/+ mice. Ablation of CCR2 in ApcMin/+ mice significantly increased the survival, reduced tumor burden and corrected immune abnormalities caused by ApcMin/+ mutation. Immune cell analysis in spleen and mesenteric lymph nodes (mLNs) suggested that CCR2−/−ApcMin/+ mice exhibited significant reduction in myeloid cell population and increase in IFNγ producing T-cell populations compared to ApcMin/+ mice. CCR2−/−ApcMin/+ mice also displayed decreased tumor infiltrating F4/80+ and increased CD8+ cells. Polyps in CCR2−/−ApcMin/+ displayed significant reduction in IL-17 and IL-23 cytokines compared to polyps of ApcMin/+. Adoptive transfer of splenic CD4+ T cells from ApcMin/+ mice into Rag2−/− mice develops severe colitis. However, transfer of CD4+ T cells from CCR2−/− ApcMin/+ failed to develop colitis in Rag2−/− mice. The levels of IL-17 in these mice significantly reduced suggesting importance of CCR2 expression on CD4+cells to promote IL 17 mediated colonic inflammation. Microbiota analysis revealed that ablation of CCR2 in ApcMin/+ lead to decrease in tumor promoting Bacteroides genus compared to ApcMin/+. In conclusion, CCR2 plays a critical role in enhancing tumor-promoting inflammation via IL-17 and IL-23 leading to increased intestinal tumorigenesis in ApcMin/+ mice. Blocking CCR2-CCL2 axis potentially offers an alternative therapeutic option to control intestinal tumorigenesis.
Mucosal immune responses to b-lactoglobuin (βLG)-immunized mice are altered following colitis challenge
Authors: Zlotkowska Dagmara Anna , Wasilewska Ewa , Wroblewska Barbara 
Published: January 2023

Abstract
Food allergens induce mucosal immune responses, and their continual exposure to sensitive hosts leads to health problems, e.g. intestinal inflammation. We tested dextran sodium sulfate (DSS) to disrupt intestinal homeostasis in mice immunized with βLG.
BALB/c mice were ip. sensitised with βLG/PBS, thereafter orally challenged with βLG. DSS was delivered in drinking water et libitum. Humoral response and T cell profile were monitored for differences in immune response between groups. The highest level of Ag-specific serum IgG was observed in the i.p. immunized group without dependence on DSS presence. The level of Ag-specific IgA in sera and fecal extracts was low in each group. We found the greatest amount of CD4+ and FoxP3+CD25+CD4+ T cells in the spleens, mesenteric and peripheral lymph nodes obtained from mice orally immunized with βLG and receiving DSS treatment. DSS also induced a subset of CD4+ T cells producing a high amount of IFN-γ in all experimental groups. An elevated number IFN-γ+ CD4+ T cells was found in the lymphoid tissues of βLG-immunized mice (ip and orally) and treated with DSS. The profile of peripheral blood lymphocytes showed a two-fold increase in FoxP3+CD25+CD4+ T cells after DSS stimulation.
The proposed experimental model of the inflamed intestine provoked with allergens showed differences in humoral responses and lymphocyte profiles, demonstrating that this regimen can be used to monitor immunoreactivity to food compounds.
MERTK inhibition in the leukemia microenvironment promotes a therapeutic immune response to acute lymphoblastic leukemia
Authors: Jacobsen Kristen M , Lee-Sherick Alisa B. , Huey Madeline G. , Page Lauren S. , Zhang Weihe , Wang Xiaodong , Fyre Stephen V. , Earp H. Shelton , Jordan Craig T. , DeRyckere Deborah , Graham Douglas K. 
Published: January 2023

Abstract
T cell immunotherapy is effective in some, but not all cancers, and targeting the immunosuppressive, innate immune tumor microenvironment is one key to further advancement. During efferocytosis, activation of MERTK tyrosine kinase receptor in innate immune cells suppresses proinflammatory cytokines, stimulates immunosuppressive cytokines and upregulates co-inhibitory ligands. MERTK has also been validated as a therapeutic target in the tumor microenvironment in solid tumor models. To investigate immunoregulatory roles for MERTK in leukemia, we utilized pharmacologic and genetic inhibition of MERTK in a MERTK-negative syngeneic murine model of acute lymphoblastic leukemia (ALL). Treatment with MRX-2843, a potent, orally bioavailable, small molecule MERTK inhibitor, significantly reduced leukemic burden and prolonged median survival in wildtype mice (38 days post-treatment vs. 24 days in vehicle-treated mice, p&gt;0.01). Similarly, overall survival was increased more than four-fold in Mertk−/− mice transplanted with leukemia (&gt;80 days vs. 21 days in wild-type mice, p&gt;0.0001), suggesting that the observed therapeutic activity is immune-mediated. Indeed, treatment with MRX-2843 abrogated expression of the immune co-inhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the ALL microenvironment. Although T cells do not express MERTK, expression of the cognate PD-1 receptor was also reduced on CD8+ T cells and the frequency of FOXP3+CD4+ regulatory T cells was decreased in the leukemia microenvironment following MRX-2843 treatment. These data demonstrate several mechanisms by which MERTK can suppress anti-leukemia immunity and validate MERTK as a novel immunotherapeutic target in ALL.
Topical chemo-immunotherapy converts a pro-tumorigenic tumor microenvironment to a pro-inflammatory phenotype in human cutaneous squamous cell carcinoma
Authors: Friedman Blake , Carey Cara , Erdos Geza , Falo Louis D. 
Published: January 2023

Abstract
We have previously demonstrated that microneedle array (MNA) delivery of anti-tumor agents improves survival in mouse models of melanoma and non-melanoma skin cancers and induces cell death in freshly excised human cutaneous squamous cell carcinomas (cSCCs). As tumors employ strong immunosuppressive and tumor-promoting mechanisms that prevent their elimination by immune surveillance mechanisms and support their proliferation, we sought to determine if application of MNAs containing anti-tumor agents could abrogate their protumorigenic phenotype and promote an anti-tumor phenotype in a human model of cSCC, the second most common human malignancy worldwide. To accomplish this, we compared Nanostring gene expression data from human cSCCs treated with MNAs containing doxorubicin (MNA-Dox) to matched, untreated cSCC controls and unmatched normal skin. As compared to matched, untreated cSCC controls, MNA-Dox-treated cSCCs demonstrated significantly decreased expression of genes associated with a pro-tumorigenic environment, including IDO, ARG2, S100A7 and VEGF-A. Further, MNA-Dox-treated cSCCs demonstrated significantly increased expression of genes associated with an anti-tumor phenotype, including CXCL14, HMGB1, P53, and Caspase-8. Comparison of MNA-Dox-treated cSCCs and unmatched, untreated normal skin suggested a reversion of a pro-tumorigenic phenotype to a normal skin phenotype, with similarly low expression of pro-tumorigenic genes seen in both groups. Together, these results suggest the potential of MNA-administered doxorubicin to effectively transform a pro-tumor microenvironment to one favoring the induction of tumor immunity in a human cSCC.
IL-22 Promotes Pancreatic Cancer Tumorigenesis through Induction of Stemness and Epithelial to Mesenchymal Transition
Authors: Lanfranca Mirna Perusina , Kryczek Ilona , Rhim Andrew , Girgis Alexander , Lazarus Jenny , Di Magliano Marina Pasca , Zou Weiping , Frankel Timothy 
Published: January 2023

Abstract
Elevated levels of Interleukin 22 (IL-22) and its receptor (IL-22R) are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC) and the underlying mechanism is currently unknown. Our aim is to investigate the role of the IL-22 axis in PDAC initiation and progression.
Impact of IL-22 on tumor initiation was assayed by subcutaneous and intravenous inoculation of PDAC cells into wild-type and IL-22−/− mice. The PKCY (Pdx1-Cre; KrasG12D; p53fl/+; RosaYFP) model of pancreas cancer was used to study the in-vivo presence and significance of IL-22 in spontaneous tumors. Results were confirmed in human specimens of surgically resected pancreas cancer.
IL-22R was present in all tested PDAC lines and IL-22 treatment led to STAT3 phosphorylation and subsequent increased expression of EMT (Epithelial to Mesenchymal Transition) transcription factors. Cells transitioned to a mesenchymal phenotype and robust tumor sphere formation was observed. While tumors readily formed in wild-type mice, initiation, establishment and growth were impaired in IL-22−/− mice and PKCY-IL-22−/− mice. Increased levels of IL-22 were found in both spontaneous murine tumors and surgical specimens compared to control tissue. IHC of tumors showed diffuse IL-22R staining with increasing intensity of pSTAT3 and EMT markers as tumors progressed to invasive cancer. FACS analysis identified type 3 innate lymphoid cells and TH22 cells as the source of IL-22 in both human and murine PDAC.
Our data suggests that IL-22 is integral in the initiation, progression and establishment of pancreatic cancer, positioning it as an attractive target for cancer therapy.
Activation of cannabinoid receptors alters the expression of miRNAs in Granulocytic Myeloid Derived Suppressor cells (G-MDSCs) and Splenic Resident Granulocytes (SRG) thereby identifying shared and unique pathways of differentiation
Authors: Singh Narendra Prasad , Miskin Arianna , Singh Udai P , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
THC (Δ9-Tetrahydrocannabinol) is the main psychotropic component in marijuana and has been shown to have potent anti-inflammatory properties. Recent studies from our laboratory have shown that THC triggers massive induction of myeloid derived suppressor cells (MDSCs) through modulation of miRNA(miR). In this study, we investigated the effect of THC on the regulation of miRs in Granulocytic MDSCs (G-MDSCs) and splenic resident Granulocytes (SRG) in mice. To this end, mice (C57BL/6) were treated with vehicle or THC (20 mg/kg bw) and 24 hrs post injection, G-MDSCs from peritoneal wash and SRG from spleen were sorted (&gt;95% purity) and microRNA arrays were performed using total RNAs including miRs. There was significant alterations in the expression of about 75 miRs in both G-MDSCs and SRG. Out of the 75 miRs, 31 miRs were upregulated and 9 miRs were downregulated in both G-MDSCs and SRG. There were 21 miRs that were downregulated in G-MDSCs but upregulated in SRG. The remaining 14 miRs were upregulated in G-MDSCs but downregulaed in SRG. Upon analysis of dysregulaed miRs using IPA, there were more than 20 diseases and pathways that were regulated by these miRs. We also observed that dysregulatd miRs played a common role in the development of several diseases including cancer and inflammatory diseases. This study demonstrate for the first time that THC regulates miRs that are both shared and unique to G-MDSCs and SRGs, thereby suggesting that while G-MDSCs are similar in some ways to SRGs, they may be at different stages of differentiation.
The present study was supported in part by NIH grants (P20GM103641, P01AT003961, R01AT006888, R01ES019313, and R01MH094755).
Mincle regulates autophagy to control neutrophil extracellular trap formation
Authors: Sharma Atul , Simonson Tanner J , Jondle Christopher N. , Mishra Bibhuti B. , Sharma Jyotika 
Published: January 2023

Abstract
“Neutrophil extracellular traps (NETs) constitute antimicrobial function of neutrophils but have also been linked to perpetuation of inflammation. Despite this evident physiological relevance, mechanistic understanding of NET formation is poor. In the current study we examined the mechanism by which Mincle, a C-type lectin receptor, regulates NET formation. We found that Mincle mediates NET formation in response to several activation stimuli in-vitro and in-vivo during pneumoseptic infection with Klebsiella pneumoniae, indicating its regulatory role in NET formation. Mechanistically, we show that attenuated NET formation in Mincle−/− neutrophils correlates with an impaired autophagy activation in-vitro and in-vivo, while reactive oxygen species (ROS) formation in these neutrophils remained intact. The requirement of autophagy in Mincle-mediated NET formation was further supported by exogenous treatment with autophagy inducer tamoxifen, which rescued the NET formation defect in Mincle−/− neutrophils. Our findings identify a previously unrecognized role of Mincle as a regulator of autophagy which mediates NET formation without affecting ROS generation. Our study addresses a major challenge in the field by positing this pathway to be targeted for modulation of NETs, while preserving ROS production, an important innate immune defense.”
Prediction, molecular modelling and dynamic simulations of Vascular endothelial growth factor receptor 1 as a potential molecular target for 2,3,7,8-tetrachlorodibenzo-pdioxin
Authors: Chitrala Kumarswamy naidu , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Dioxins are ubiquitous, persistent environmental pollutants known to accumulate in fat. 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immunotoxicity and promotes the differentiation regulatory T cells and inhibits the Th17 cells. To date, studies on only few molecular targets for TCDD are available, thereby limiting the understanding of the exact mechanism of action on immune response. To that end, in the present study, we have predicted the molecular targets for TCDD using knowledge-based approach and reverse pharmacophore mapping approach, and analyzed the mechanism underlying receptor conformational changes following the binding of TCDD using molecular modelling and molecular dynamic simulation (MDS) studies. Results showed that 11 potential target candidates predicted in Mus musculus and 20 in Homo sapiens with Vascular endothelial growth factor receptor 1 (VEGFR1) being the high probability target for TCDD in both Mus musculus and Homo sapiens. Results from molecular docking studies showed that TCDD interacts with a binding energy of −7.37 kcal/mol with mouse VEGFR1 and −6.55 kcal/mol with human VEGFR1. Four independent MDS studies revealed key interactions and major secondary structural changes for both mouse and human VEGFR1-TCDD complexes, specifically at residues in α-helices and coils for human VEGFR1-TCDD complex. In conclusion, this study defines VEGFR1 as a potential molecular target candidate for TCDD and establishes the structural basis for the VEGFR1-TCDD interactions as well as reveals that conformational changes at the onset of ligand binding may play a role in immunomodulation.