bluuebunny/crossref_metadata_2025_split huggingface dataset:
PGE2 imbalance in diabetic mice impairs dendritic cell maturation and favors methicillin-resistant S. aureus skin infection
Authors: Dejani Naiara , Brandt Stephanie , Pinneros Annie , Glosson-Byers Nicole , Wang Wang , Medeiros Alexandra , Serezani Carlos Henrique 
Published: January 2023

Abstract
Diabetics are more prone to Staphylococcus aureus skin infection than healthy individuals. Neutrophil recruitment and apoptosis are hallmarks of S. aureus infections. Ingestion of infected apoptotic cells (IAC) by dendritic cells (DC) lead to secretion of Th17-related cytokines and prostaglandin E2 (PGE2). We speculate that hyperglycemia inhibits DC migration to the lymph nodes, in a manner dependent on PGE2 levels and impairs Th17 differentiation during MRSA skin infection in type 1 diabetic mice (T1D). Control and T1D mice were subcutaneously (s.c.) infected with 5×106 MRSA CFU. T1D mice showed increased lesion and bacterial load and decreased Th17 population in the skin than nondiabetic mice. We next determined if decreased Th17 correlates with deficient DC migration to draining LN. To track DC migration, mice received s.c. FarRed to stain the skin cells. Our results show that T1D had lower percentage and number of FarRed+DCs+ in the LN than controls.. Impaired DC migration and Th17 differentiation in T1D correlated with decreased skin PGE2 levels. When BMDCs were cultured in high glucose, we observed decreased PGE2 production, migration and maturation after recognition of MRSA-IAC when compared to BMDC kept in normal glucose. Topical treatment with PGE analog (Misoprostol), restored skin DC migration, Th17 differentiation, increased anti-microbial peptides, decreased CFU loads and lesion size in T1D. These data suggest that PGE2 imbalance in hyperglycemia impairs DC migration to LN and fail to mount Th17 responses leading to increased lesions and delayed healing in MRSA skin infections. Misoprostol may be a promising candidate to improve innate and adaptive immune responses in diabetic skin infections.
Regulation of MerTK, GPNMB, and VSIG4 on mouse macrophages
Authors: Del Cid Natasha , Stepniak Dariusz T , Ferrer Allison , Scott Brad , Magana Jonathan , Li Xiaoxiao , Ma Lisa , Miranda Cherlyn , Li Shourong , Schrantz Nicolas , Huang Qiulong , Becker-Catania Sara , Funatake Castle J , Just Peggy 
Published: January 2023

Abstract
We have developed flow cytometry antibodies against three molecules expressed on tissue-resident mouse macrophages: MerTK, GPNMB (aka Osteoactivin, DC-HIL), and VSIG4 (aka CRIg). MerTK, a receptor tyrosine kinase, plays a crucial role in the clearance of apoptotic cells, as well as in the regulation of cytokine secretion and survival. MerTK is highly expressed by splenic red pulp macrophages, which aid in the clearance of apoptotic cells in the blood. GPNMB, a transmembrane glycoprotein, plays a role in negatively regulating cytokine secretion during inflammatory responses and is expressed on tissue-resident macrophages, including microglia. Finally, VSIG4, a B7 family-related complement receptor, negatively regulates T cell-mediated responses and is also expressed on tissue-resident macrophages. The three clones DS5MMER (MerTK), CTSREVL (GPNMB), and NLA14 (VSIG4), were validated using resident and thioglycollate-elicited peritoneal exudate cells. DS5MMER (MerTK) and NLA14 (VSIG4) were also validated by IHC using frozen mouse tissue samples. Here, we have measured surface levels of MerTK, GPNMB, and VSIG4 on mouse bone marrow-derived macrophages by flow cytometry in response to an array of cytokines. We have also assessed the distribution of MerTK- and VSIG4-positive cells in various mouse tissues. Our data show how MerTK, GPNMB, and VSIG4 respond to various pro- and anti-inflammatory conditions in mouse bone marrow-derived macrophages and gives insight into how these receptors may be regulated on mouse macrophages in vivo.
LPS-induced interaction between Cd300b/DAP12 and TLR4/CD14 results in the amplification of inflammation and increased mortality from sepsis.
Authors: Voss Oliver H. , Coligan John E. 
Published: January 2023

Abstract
LPS, present in gram-negative bacteria membranes, causes a strong immune cell activation following detection by TLR4, which initiates a pro-inflammatory cytokine storm that leads to a more severe immunopathology, like septic shock and, subsequently, death. Recently, the myeloid-specific Cd300b receptor was implicated in regulating the immune response to bacterial infection by an unknown mechanism.
Here, we identified LPS as a ligand for Cd300b and found that wild-type (WT) mice, unlike Cd300b−/− mice, were highly susceptible to septic shock. WT but not Cd300b−/− mice show increased serum levels of pro-inflammatory cytokines (e.g. TNFa) and a reduced level of the anti-inflammatory cytokine, IL-10. Neutralization of IL-10 in Cd300b−/− mice diminishes their survival advantage over WT mice. In vivo depletion and adoptive transfer studies identify Cd300b-expressing macrophages as the key cell type augmenting septic shock, suggesting that Cd300b amplifies the TLR4-LPS induced immune response thereby causing lethal inflammation. Indeed, Cd300b and its adaptor, DAP12, associated with TLR4/CD14 upon LPS binding, promoting MyD88/TIRAP dissociation and the recruitment and activation of Syk and PI3K. This results in the activation of AKT, which subsequently leads to a reduced IL-10 production, via a PI3K/AKT-dependent inhibition of the MEK1/2-ERK1/2 signaling pathway.
In sum, these findings describe a previously unidentified LPS-induced signaling complex consisting of Cd300b/DAP12/TLR4/CD14/Syk/PI3K that effectively amplifies TLR4/CD14-mediated inflammation. Furthermore, our data change the paradigm of how LPS mediates TLR4 signaling in myeloid cells and identify potential targets for future clinical intervention.
Targeting chromatin kinases reveals their role in inducible transcription of inflammatory genes
Authors: Josefowicz Steven , Shimada Miho , Armache Anja , Li Charles , Miller Rand , Lin Shu , Garcia Benjamin , Taunton Jack , Roeder Robert , Allis David 
Published: January 2023

Abstract
The inflammatory response requires selective, rapid regulation of chromatin and induction of transcription for defense against pathogens and environmental insult, and also features abundant kinase activity. We sought to identify the connections between kinase pathway activity and regulation of chromatin through unbiased identification and genomic foot printing of prominent histone phosphorylation events. We identified histone H3 serine 28 phosphorylation (H3S28p) as the principal stimulation-dependent histone modification with enrichment at induced inflammatory genes in mouse macrophages stimulated with bacterial lipopolysaccharide (LPS). Use of chemical inhibitors and genetic rescue identified mitogen- and stress-activated protein kinases (MSK) as the primary mediators of H3S28p in macrophages. Cell-free transcription assays demonstrated that H3S28p directly promotes transcription. Further, we show that MSK can activate both signal-responsive transcription factors and the chromatin template with additive effects on transcription. Indeed, inhibition of MSK in macrophages selectively reduced transcription of stimulation-induced genes. Our results indicate MSK as a nexus of signaling inputs controlling multiple downstream regulators of inducible transcription.
Rapid transcriptional reprogramming of the lipid biosynthesis genes in response to type I interferon
Authors: York Autumn Gabrielle , Williams Kevin J. , Liu Xin , Argus Joseph P. , Tong Ann-Jay , Zhou Quan D. , Smale Stephen T , Bensinger Steven 
Published: January 2023

Abstract
Cellular lipid requirements are achieved through a combination of biosynthesis and import programs. In previous studies, we found that type I interferon (IFN) signaling shifts the balance of these programs by decreasing synthesis and increasing import of cholesterol and long chain fatty acids. Genetically enforcing this metabolic shift in macrophages alone was sufficient to render mice resistant to viral challenge, demonstrating the importance of reprogramming the balance of these two metabolic pathways in vivo. However, it currently remains unclear how type I IFN signaling rewires lipid metabolism. Here, we show that type I IFN-mediated changes in lipid metabolism occur rapidly at the level of transcription. Systematic studies identified a reduction in primary transcripts of lipid synthesis genes within 30 min post IFN. Mechanistically, we find that the rapid transcriptional reprogramming of lipid synthesis is driven by STAT2, independent of the ability of STAT2 to regulate Ch25h and other interferon stimulated gene (ISG) expression. These observations suggest that STAT2 functions to negatively regulate lipid synthesis genes while concurrently upregulating ISG expression. Thus, we propose a model where type I IFN-mediated activation of STAT2 results in the rapid displacement of the canonical transcriptional regulators of lipid metabolism. As such, activation of STAT2 negatively regulates flux through the lipid biosynthetic pathway. On going studies aim to elucidate the precise changes in promoter occupancy of the lipid synthesis genes in response to type I IFN signaling. In sum, these studies indicate that direct manipulation of lipid homeostasis is intimately intertwined with canonical host defense signaling cascades.
TNF Receptor 2 on CD8+ T cells and TNF receptor 1 on non-CD8+ T cells Contribute Significantly to Chlamydia pneumoniae-Induced Atherosclerosis
Authors: Manam Srikanth , Zafiratos Mark T , Cottrell Jonathan T , Henderson Kyle K , Ramsey Kyle H , Murthy Ashlesh K 
Published: January 2023

Abstract
Chlamydia pneumoniae is an important cause of community-acquired pneumonia and has been associated with exacerbation of atherosclerosis. A role of TNF-α in Chlamydia pneumoniae (Cpn) induced atherosclerosis has been reported previously; however, the relative contribution of the two cognate receptors of TNF-α, TNF receptor 1 (TNFR1) and TNFR2 had not been studied. In the current study, C57BL/6J (WT) mice, TNFR1, TNFR2 and TNFR1/2 DKO mice were infected intranasally on days 0, 14 and 28 with 1 × 107 IFU of Cpn (AR39) and were fed a high fat (HF) diet throughout the experiment. One group of WT mice were mock infected with PBS as a control. All Cpn-infected KO mice displayed serum anti-Cpn antibody response, splenic cellular Cpn-specific IFN-γ and TNF-α response, and serum total cholesterol levels comparable to infected WT animals. On day 100 following infection, Cpn infected TNFR1, TNFR2 and TNFR1/2 DKO mice displayed significantly reduced atherosclerotic pathology compared to infected WT mice, and at levels comparable to mock-infected WT animals., suggesting that TNFR1 and TNFR2 play a significant role in Cpn-induced atherosclerosis. We demonstrated recently that CD8+ T cells induce Cpn-mediated atherosclerosis; therefore, we further investigated the role of TNFR1 and TNFR2 on CD8+ T cells in pathogenesis. TNFR2 KO mice, not TNFR1 KO mice, replete with WT CD8+ T cells displayed enhancement of atherosclerotic pathology to levels observed in Cpn-infected WT animals. Collectively, these results demonstrate that TNFR2 on CD8+ T cells and TNFR1 on non-CD8+ T cells contribute significantly to Chlamydia pneumoniae induced atherosclerosis.
Enhanced T cell responses to IL-6 in type 1 diabetes are associated with early clinical disease and increased IL-6 receptor expression
Authors: Hundhausen Christian , Roth Alena , Whalen Elizabeth , Chen Janice , Schneider Anya , Long Alice , Wei Shan , Greenbaum Carla J. , Cerosaletti Karen , Buckner Jane H. 
Published: January 2023

Abstract
IL-6 is a key pathogenic cytokine in multiple autoimmune diseases including rheumatoid arthritis and multiple sclerosis, suggesting that dysregulation of the IL-6 pathway may be a common feature of autoimmunity. The role of IL-6 in type 1 diabetes (T1D) is not well understood. Here we show that STAT3 and STAT1 responses to IL-6 are significantly enhanced in CD4 and CD8 T cells from individuals with T1D compared to healthy controls. The effect is IL-6 specific as it is not seen with IL- 10 or IL-27 stimulation, two cytokines that signal via STAT3. An important determinant of enhanced IL-6 responsiveness in T1D is IL-6 receptor surface expression, which correlated with phospho-STAT3 levels. Further, reduced expression of the IL-6R sheddase ADAM17 in T cells from patients indicated a mechanistic link to enhanced IL-6 responses in T1D. Interestingly, IL- 6- induced STAT3 phosphorylation was inversely correlated with time from diagnosis, suggesting that dysregulation of IL-6 signaling may be a marker of early disease. Finally, whole-transcriptome analysis of IL-6 stimulated CD4+ T cells from patients revealed novel IL-6 targets involved in T cell migration and inflammation, including lymph node homing markers CCR7 and L-selectin. In summary, our study demonstrates enhanced T cell responses to IL-6 in T1D due in part to an increase in IL-6R surface expression. Dysregulated IL-6 responsiveness may contribute to diabetes through multiple mechanisms including altered T cell trafficking and indicates that individuals with T1D may benefit from IL-6 targeted therapeutic intervention such as being currently tested (NCT02293837).
Type I interferon signalling suppresses anti-parasitic CD4+ T cell responses during visceral leishmaniasis
Authors: Kumar Rajiv , Bunn Patrick , Singh Neetu , Sundar Shyam , Engwerda Christian 
Published: January 2023

Abstract
Many pathogens, including viruses, bacteria, and protozoan parasites, suppress cell mediated immune responses through activation of type I Interferon (IFN-1) signalling. However the role of IFN-1 during Leishmania donovani infection causing visceral leishmaniasis (VL) is not well known. Here we report that IFN-1 play an important role in the pathogenesis of VL by impairing parasite clearance and suppressing pro-inflammatory cytokine production. Mice lacking type-1 IFN signalling (B6.IFNαR1−/− mice) had enhanced pro-inflammatory cytokine production and better control of parasite burden in liver as well as spleen compared to wild type C57BL/6 mice. IFN-1 signalling suppressed the CD4+ derived IFN-γ production and prevented Th1 response from controlling parasite replication. Experiment using bone marrow chimeric mice revealed that IFN-1 did not suppress CD4+ T via directly acting to this cell type. Using conventional dendritic cell (cDC) specific IFN-1 deficient mice (CD11c Cre-IFNARfl/fl), we observed that IFN-1 hampered CD4+ T cells response acting via dendritic cells. Studies in VL patients supported these findings and showed enhanced accumulation of mRNA encoding type I IFN signature genes in peripheral blood mononuclear cells (PBMCs) that were reduced following successful drug therapy. Critically, we also showed, using a whole blood assay, that blockade of type-1 IFN signalling enhanced antigen specific IFN-γ production, and that this response was HLA-II restricted. Together, these results identify the type-1 IFN signalling pathways as a potential therapeutic target to treat VL by stimulating anti-parasitic CD4+ T cell responses.
MALT1-deficient CD4 T cells exhibit decreased IL-2 secretion and impaired Th1 and Th17 differentiation
Authors: Kang Sohyeong , Huang Yu-Husan , Wang Xiaoxia , Fung Shan-Yu , Turvey Stuart , Priatel John J 
Published: January 2023

Abstract
A child admitted to British Columbia Children’s Hospital displayed a novel clinical presentation of immune dysregulation, exhibiting lymphocytic infiltration and severe inflammation of the intestinal tract and other mucosal surfaces. Whole-exome sequencing revealed that the patient inherited missense MALT1 mutations and her lymphocytes exhibited deficits in MALT1 protein and MALT1-dependent signal transduction. MALT1 plays critical roles in T cell receptor signal transduction through at least two different mechanisms: (1) as a signaling adaptor molecule bringing together CARMA-1 and BCL-10 to form the CBM signalosome complex and (2) as a caspase-like protease (paracaspase) cleaving substrates after arginine residues. Studies on Malt1−/− mice have revealed diminished NF-KB activation and weakened T cell immunity whereas mice lacking paracaspase activity but not MALT1 adaptor function are prone to lethal autoimmunity. Altogether, these mouse findings raise questions regarding the nature of our patient’s mutant MALT1 protein and the role it plays in her proinflammatory phenotype. Consequently, we plan to analyze our patient’s MALT1 mutation by investigating the paracaspase activity, signaling, and function of her T cells. Early studies have found that patient CD4 T cells exhibit defects in Th1 and Th17 differentiation and these impairments could be responsible for inefficient immune responses leading to chronic infections. Finally, a better understanding of MALT1 will provide insight into inflammatory disease and prove invaluable in supporting MALT1-targeted therapies to modulate T cells to treat autoimmune diseases.
Wellness Index: measuring the readiness of our immune system
Authors: Han Jian 
Published: January 2023

Abstract
We performed next generation sequencing on 1000 individuals’ immune repertoires. More than 3 billion T cell receptors beta chain sequences were obtained from peripheral blood samples. Over 75 million unique CDR3 sequences were identified. The majority of the CDR3 sequences (81%) were private and not shared. However, a few thousand of the CDR3 sequences were classified as very public and shared by almost everyone. Taking advantage of this knowledge, we developed a Wellness Index to measure the readiness of our immune system in fighting different diseases. A person’s Wellness Index (WI) equals to the number of the top 1000 very public CDR3s (pCDR3s) found in his/her sample. The more pCDR3s found in a unit blood, the more diversified the immune repertoire, and therefore, the more healthy or more ready to ward off diseases. Although the Wellness Index does not diagnose specific diseases, it provides an accurate and reliable measurement of health status. The Wellness Index may also be associated with cancer patient’s outcomes or responses to different treatments.
The changes of gene expression between pulmonary tuberculosis lesions and normal tissue
Authors: CHUANYOU LI , li wensheng , sun yong 
Published: January 2023

Abstract

Objective
to develop specific genes associated with the formation of these severe tuberculosis lesions by comparing gene expression changes of macrophages between the lesions and normal lung tissue around it

Material and methods
select lesions tissue and surrounding normal lung tissue specimens from three tuberculosis patients, magnetic bead separation method was applied to filter out the macrophages within the organization, extracted RNA and detected with gene chip to contrast the difference of gene expression patterns. between the lesions and surrounding normal lung tissue

Results
there were 332 genes up regulation and 102 genes down regulation to 2 fold in normal lung tissues. making the selecting criteria rising to 4 fold, the number of up regulation and down regulation genes would decrease to 19 and 2. The two down regulation genes were FER1L4 and PPIL5. During the up regulation group. the AREG gene was very special because the up regulation fold of this gene in our three groups were more than 11 times respectively. Moreover, the expression level of four genes which were related with TNF were obviously up regulationd in normal lung tissues

Conclusion
PPIL5, AREG and TNF may be associated with the formation of pulmonary tuberculosis lesions.
High frequencies of Caspase-3-expressing M. tuberculosis-specific CD4 T cells are associated with active tuberculosis
Authors: Adekambi Toidi , Ibegbu Chris , Cagle Stephanie , Ray Susan , Rengarajan Jyothi 
Published: January 2023

Abstract

Background
The identification and treatment of individuals with tuberculosis (TB) is a global public health priority. Accurate diagnosis of pulmonary active TB (ATB) disease remains challenging and relies on extensive medical evaluations and detection of Mycobacterium tuberculosis (Mtb) in the patients’ sputum. Further, the response to treatment is monitored by sputum culture conversion, which takes 3–6 weeks for results. Here, we sought to identify blood-based host biomarkers associated with ATB and hypothesized that frequencies of Mtb-specific CD4+IFN-g+ T cells expressing caspase-3 would decrease following anti-TB treatment. Caspase-3, a member of cysteine proteases’ family, is highly expressed in CD4 effector T cells and has been shown to regulate T cell activation, cell cycle entry, proliferation and apoptosis.

Methods
Using polychromatic flow cytometry, we evaluated the expression of the active form of caspase-3 on Mtb-specific CD4+ T cells from individuals with asymptomatic latent Mtb infection (LTBI) (n=22), ATB (n=18), and from ATB patients undergoing anti-TB treatment (n=7).

Results
Frequencies of Mtb-specific IFN-g+CD4+ T cells that expressed active caspase-3 were higher in individuals with ATB compared to those with LTBI suggesting that apoptotic pathways are operant during pulmonary ATB. This marker also distinguished individuals with untreated ATB from those who had successfully completed anti-TB treatment and correlated with decreasing mycobacterial loads during treatment.

Conclusion
We have identified caspase-3 on Mtb-specific CD4+ T cells as a marker that distinguishes ATB and LTBI and may provide a tool for monitoring treatment response and cure.
Circulating T cells specific for an intestinal bacterial antigen peptide show a distinctive phenotype and potentially proinflammatory gene expression pattern in Crohn’s disease.
Authors: Uchida Amiko M , Boden Elisa , Shows Donna , James Eddie A , Lord James D 
Published: January 2023

Abstract

Background
Crohn’s disease (CD) may be an inappropriate immune reaction to normally well-tolerated intestinal bacterial antigens. Indeed, many CD patients possess abnormally high titers of antibodies specific for intestinal bacterial proteins, such as the outer membrane protein C (OmpC) of E. coli.

Methods
Using MHC-II tetramer-guided epitope-mapping, we identified a specific peptide of OmpC recognized by peripheral T cells from HLA-DR1501+ individuals. HLA-DR1501 tetramers loaded with this OmpC peptide or a known antigenic peptide from influenza virus (Flu) were then used to compare OmpC versus Flu-specific T cells from HLA-DR1501+ healthy and CD donors via flow cytometry and multiplex qPCR.

Results
OmpC-specific T cells more frequently expressed the Th17 marker CD161 (49% v 26%; p=1.1e-18) and the gut-homing integrin α4β7 (43% v 10%; p=1.8e-13) than autologous Flu-specific T cells. Conversely, the Th1 marker CXCR3 was more commonly seen on Flu than OmpC-specific T cells (72% v 61%; p = 0.005). No differences in the frequency or immunophenotype of OmpC-specific T cells were found between healthy and CD patients. However in patients with CD, multiplex PCR of sorted OmpC-specific T cells revealed significantly higher expression of the costimulatory molecule CD226 (p=0.03) compared to healthy controls, with a concomitant trend towards decreased expression of the coinhibitory receptor TIGIT (p=0.1) in CD patients.

Conclusions
OmpC-specific T cells with a gut-tropic, Th17-like phenotype can be found in the peripheral blood, and may have an imbalance in CD226 and TIGIT expression to favor inflammation in CD.