bluuebunny/crossref_metadata_2025_split huggingface dataset:
Casapse-1 is not required for the induction of Silica-induced autoimmunity
Authors: Pawar Rahul D. , Mayeux Jessica , Cooper Timothy , Awad Alaa S. , Kono Dwight H , Pollard Kenneth M. 
Published: January 2023

Abstract
Occupational exposure to respirable crystalline silica induces silicosis in humans & has been associated with lupus (SLE), but the specific mechanisms & susceptibility factors are largely unknown. Recent studies have highlighted a prominent role for interleukin-1β in silica-induced lung inflammation. Caspase-1 is predominantly involved in the cleavage of pro-IL-1β to active IL-1β. Therefore, we investigated the role of IL-1β in the severity of lung damage & autoimmune response to silica by exposing B10.S and Caspase-1 deficient B10.S (B10.S-Casp1−/−) mice to crystalline silica (1 mg in 25 μl) in PBS or PBS only, by intranasal instillation twice a week for 4 weeks. When analyzed for autoimmunity at 28 weeks post-exposure, both B10.S and B10.S-Casp1−/− mice developed similar elevated levels of anti-chromatin & anti-nuclear antibodies in serum & broncho-alveolar lavage (BAL) compared to PBS controls. Correspondingly, both silica-treated B10.S and B10.S-Casp1−/−mice had a significant peribronchial & perivascular lymphocytic infiltrates (PLI), alveolar proteinosis (AP), and alveolitis, but the PLI and AP were significantly higher in B10.S mice than B10.S-Casp1−/−mice. Similarly, robust increases in the levels of total protein & cell numbers in BAL fluid, but total protein was significantly higher in B10.S mice than B10.S-Casp1−/−mice. Higher numbers of inflammatory M1 macrophages (CD11b+Ly6chi) & neutrophils (Ly6Ghi) were also observed in both groups of silica-treated mice. These findings indicate that caspase-1 and by inference IL-1β is not required for silica-induced autoimmunity in mice, but contributes to the lung inflammation, & suggests that NLRP3 inflammasome, cathepsin C, elastase, granzyme B may be more important.
Influenza vaccine induces anti-nuclear and anti-double strand DNA IgG antibodies and their relates to levels of microbial translocation in antiretroviral-treated aviremic HIV-infected patients but not in healthy controls
Authors: Luo Zhenwu , Martin Lisa , Kilby Michael , Liu Hui , Jin Ping , Stroncek David , Jiang Wei 
Published: January 2023

Abstract

Background
The mechanism of autoreactive antibody induction in HIV disease is unknown.

Methods
In this study, blood samples from healthy controls (n = 16) and antiretroviral therapy (ART)-treated HIV infected patients (n = 26) receiving 2013–2014 seasonal influenza vaccine were analyzed pre-vaccination (D0) and post-vaccination (D14). B cell function, LPS, 16S rDNA, anti-nuclear IgG (ANA, OD) and anti-dsDNA (IU/ml) IgG in plasma were evaluated. Data are presented as median (interquartile range [IQR]).

Results
At baseline, there were increased frequencies of B cell apoptosis and cycling expression, and increased plasma LPS [pg/mL, 18.0 (13.3–22.0) vs 13.4 (9.82–15.2), P = 0.006] in patients compare with controls. Bacterial 16S rDNA tended to be higher in patients compared with controls [copies/μL, 38.2 (30.3–44.9) vs 27.8 (2.3–53.6), P = 0.18]. B cells of patients exhibited increased TLR2 and 4 expression compared with controls, and TLR signaling pathway activation by microarray on D0. Plasma ANA levels on D0 and D14 were 0.31 (0.25–0.41) and 0.58 (0.31–1.29) versus 0.32 (0.23–0.40) and 0.31 (0.24–0.38), anti-dsDNA IgG levels on D0 and D14 were 15.2 (8.06–23.7) and 20.2 (13.0–50.7) versus 15.3 (12.3–37.1) and 15.5 (13.0–36.7) in patients and controls respectively. Only patients showed significant increase of both auto-IgG post-vaccination (P &lt; 0.001). Direct correlations between plasma LPS and ANA (r = 0.48, P = 0.01), and plasma 16S rDNA and anti-dsDNA IgGs (r = 0.44, P = 0.04) were found only in patients.

Conclusion
B cell function in HIV patients is not fully recovered by ART treatment, as reflected by producing autoreactive Abs in response to influenza vaccinations and its correlates with levels of microbial translocation.
GM-CSF is not required for EAE induction but contributes to both brain and spinal cord inflammation
Authors: Pierson Emily , Goverman Joan 
Published: January 2023

Abstract
Myelin-specific CD4+ T cells initiate inflammation in the central nervous system during induction of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. CD4+ T cell pathogenesis has been attributed to the secretion of various cytokines, including IL-17, GM-CSF, and IFN-γ. The relative importance of these CD4+ cytokines in EAE has been the subject of numerous studies, and in C57BL/6 and B10.PL mice, GM-CSF production by T cells is required to induce EAE, while IL-17 and IFN-γ are not required. However, our studies in C3Heb/Fej mice do not support an essential role for GM-CSF in the induction of EAE. Our model is unique in that C3Heb/Fej mice develop brain inflammation in addition to the spinal cord inflammation seen in most other EAE models. We have previously shown that IL-17 is important for (and IFN-γ inhibits) neutrophil recruitment and parenchymal inflammation in the brain of these mice, while IFN-γ promotes spinal cord inflammation. We found that GM-CSF−/− T cells were capable of inducing brain and spinal cord inflammation in wildtype recipient mice. In IL-17RA−/− recipients, wildtype T cells induce intermediate levels of brain inflammation and normal spinal cord inflammation. However, when GM-CSF−/− T cells were transferred into IL-17RA−/− recipient mice, there was a complete loss of clinical signs of brain inflammation, and spinal cord inflammation was significantly reduced, indicating that GM-CSF contributes to both brain and spinal cord inflammation. These data reveal that GM-CSF, IL-17, and IFN-γ all influence inflammation in the brain and spinal cord in C3Heb/Fej mice; while none are required, coordinately these cytokines shape CNS inflammation.
PLAG (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) regulates IL-6-STAT3 signaling to reduce neutrophil infiltration into the synovium of arthritic joints
Authors: Kim Young-Jun , Shin Jae Min , Yoon Sun Young , Kim Joo Heon , Kim Myung-Hwan , Sohn Ki-Young , Kim Heung-Jae , Han Yong-Hae , Chong Saeho , Kim Jae Wha 
Published: January 2023

Abstract
Inappropriate regulation of leukocyte trafficking can lead to impaired neutrophil clearance and increased tissue damage from the accumulation of neutrophil-secreted proteases and reactive oxygen species at the site of inflammation. In this study, we have discovered that 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) regulates the activity of signal transducer and activator of transcription 3 (STAT3), which is a master regulator of IL-6 expression. PLAG has been isolated from the antlers of Sika deer (Cervus nippon Temminck), which were known to have immunosuppressive and anti-arthritic activities. PLAG induced a significant decrease of IL-6 production in a macrophage cell line, RAW264.7, and rheumatoid arthritis-fibroblast-like synoviocyte (RA-FLS) via the regulation of STAT3 signaling. IL-6, a multifunctional pro-inflammatory cytokine, plays a critical role in the pathogenesis of joint and systemic inflammation in RA. In collagen-induced arthritis (CIA) mouse model, arthritic symptoms were recapitulated with an increase of IL-6 in the synovium, which was recuperated by the treatment of PLAG to the level comparable with commercial therapeutics (such as Remicade or Methotrexate). When the joint tissues were stained with neutrophil-specific antibodies, PLAG significantly reduced the infiltration of neutrophils into the joint synovium of CIA mouse. Therefore, PLAG inhibits the infiltration of destructive neutrophils into inflammatory sites, and can be utilized as a therapeutic agent for the treatment of sustained inflammation and joint destruction.
Dissecting the mechanisms underling acute lymphoblastic leukemia brain metastasis
Authors: Kinjo Ichiko , Bragin Denis E , Wilson Bridget S 
Published: January 2023

Abstract
Despite improved treatments, patient with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) experience relapse with devastating tumor cell dissemination into the central nervous system (CNS). As an “immune privilege site”, CNS is protected from infiltration of immune cells by specialized structure of blood-brain barrier with astrocyte endfeet that surround the blood vessels. To assess whether leukemia cells hijack mechanisms employed by inflamed immune cells to invade into the brain parenchyma, we set up leukemia mouse xenograft models with well-characterized human BCP-ALL cell lines and primary cells derived from patients. We found massive infiltration/colonization of GFP+ leukemia cells inside brain vessels and parenchyma addition to meningeal space. Immunohistochemistry staining showed that activation of astrocytes following the induction of VEGF-A in brains of leukemia burden mice. We address phenotype changes in leukemia cells, that are associated with brain metastasis by comparing the expression of chemokine receptors and cytokines in leukemia cells recovered from bone marrow and other extramedullary sites (spleen, liver) for comparison to the cells recovered from brain tissue. By investigation of extravasation steps in intact brain, we also try to figure how leukemia cells bleach the BBB and find new niche to colonize at brain parenchyma. Ongoing studies will provide new insights into the mechanisms that regulate leukemia CNS infiltration.
HUMAN LYMPH NODE DERIVED FIBROBLASTIC RETICULAR CELLS AND THEIR CHEMOKINE EXPRESSION PROFILE AFTER AN INFLAMMATORY STIMULUS
Authors: Marti Luciana C , Palomino Diana Torres , Almeida Camila Bononi , Pasqualim Denise Cunha , Cury Adriano , de Oliveira Salvalaggio Paolo Rogério , Macedo Antonio Luiz , Severino Patricia , Rizzo Luiz Vicente 
Published: January 2023

Abstract
Lymph node is a secondary lymphoid organ with highly organized and compartmentalized structure. Fibroblastic reticular cells (FRC) integrate LN structure, and are characterized by podoplanin expression (PDPN) and lack of CD31. FRCs are involved in several immune response processes but the mechanism is still under investigation. Another cell population present in the lymph node is the one lacking PDPN and CD31, so called, double negative population (DNC). FRCs and DNCs are described as chemokines producers, controlling migratory pattern and positioning of immune cells during homeostasis or inflammation. We evaluate the gene expression of human FRCs and DNCs after an inflammatory stimulus. Lymph nodes were obtained from 04 patients with different clinical diagnosis submitted to surgical procedures. All patients signed an informed consent (Approved by Ethic Committee - CAAE: 07768712.4.0000.0071). All lymph nodes were analyzed by histopathology, they were also enzymatic digested. Cells were characterized and sorted in two populations FRCs and DNCs. These cells were maintained without stimuli or stimulated with TNFα + IL-1β for 24hours. Next, RNA was extracted; gene expression was characterized using DNA Microarray. Our results demonstrate up-regulation of chemokines such as CCL2, CCL3, CCL5, CCL7 CXCL1, CXCL2, CXCL8 and CXL10 (p&lt;0.05) in both cells subsets after inflammatory stimuli, the secretion enhancement of CCL2, CCL20 and CXCL8 was confirmed by ELISA. The up-regulated expression of CCL3L3, CCL11, CCL13, CXCL5, CXCL6 only by FRCs and CCL8, CXCL3 only by DNCs, may link these cells to additional properties that need to be further investigated. These results show that FRC and DNC positively respond to an inflammatory stimulus.
Unexpected renal tissue protective role for IL-17 following disseminated candidiasis
Authors: Biswas Partha Sarathi , Ramani Kritika , Garg Abhishek V. , Conti Heather R , Whibley Natasha , Kolls Jay K , Gaffen Sarah L 
Published: January 2023

Abstract
The incidence of life-threatening disseminated Candida albicans infections is increasing in hospitalized patients, with fatalities as high as 60%. Death from disseminated candidiasis in a significant percentage of cases is due to fungal invasion of the kidney, leading to renal failure. Treatment of candidiasis is hampered by drug toxicity, the emergence of anti-fungal drug resistance and lack of vaccines against fungal pathogens. The cytokine IL-17 is known to be a key mediator of defense against candidiasis. However, the underlying mechanisms of IL-17-mediated renal immunity are poorly understood, and have to date assumed to be solely through the regulation of antimicrobial mechanisms through neutrophils. Here, we identify an unexpected role for IL-17 in inducing the Kallikrein (Klk)-Kinin System (KKS) in C. albicans-infected kidney, which we show to be a major mechanism of renal protection in this disease. Klk1 expression was upregulated in the infected kidney in an IL-17R-dependent manner. Overexpression of Klk1 or treatment with bradykinin rescued IL-17RA−/−mice from candidiasis. Therapeutic manipulation of IL-17-KKS pathways restored renal function and prolonged survival by preventing apoptosis of renal cells following C. albicans infection. Furthermore, combining a minimally effective dose of fluconazole with bradykinin markedly improved survival following candidiasis in comparison to fluconazole or bradykinin alone. These results indicate that IL-17 both limits fungal growth and prevents renal tissue damage in disseminated candidiasis via the KKS. Since drugs targeting the KKS are approved clinically, these findings offer potential avenues for treatment of this fatal nosocomial infection.
Th17/TfH cells in rheumatoid arthritis: correlations with disease activity and therapy response
Authors: McGeachy Mandy J , Singh Deepika , Henkel Matthew , Moreland Larry 
Published: January 2023

Abstract
Th17 and TfH cells are thought to promote tissue inflammation (Th17) and autoantibody production (TfH) in rheumatoid arthritis (RA) and other autoimmune diseases. TfH cells that co-express Th17 markers (Th17/TfH) correlate with disease activity in juvenile dermatomyositis. However, Th17/TfH cells have not been detailed in RA subjects in context of therapy response. Blood T cell and B cell subsets were analyzed by flow cytometry in 16 subjects with active RA, before and after TNF inhibitor therapy. Proportions of CXCR5+ TfH cells that co-expressed the Th17 marker CCR6 (Th17/TfH cells) directly correlated with disease activity at baseline. In contrast, there were no correlations between disease activity and other T cell subsets including total Th17 (CCR6+), TfH (CXCR5+) or Th1 (CXCR3+) cells, or with CXCR3-expressing TfH cells. Th17/TfH cell frequencies were unchanged by TNF inhibition, fitting with no effect of TNF on stimulation of IL-17 or IL-21 in vitro. In fact, Th17/TfH cell proportions showed remarkable stability within individuals over time despite changes in disease activity. Activated class-switched B cells were increased in subjects with high autoantibody, but B cell subsets did not correlate with disease activity or with Th17/TfH cells. Finally, baseline Th17/TfH cells correlated with numbers of swollen joints at baseline and following one year of stable therapy. These data demonstrate the stability of chemokine receptors as markers of blood T cell phenotypes within individuals, and point to differences in underlying T cell phenotypes as drivers of autoimmune joint disease activity and response to TNF inhibitor therapy.
Potential anti-nociceptive role of chemokine CXCL1 in peripheral nerve injury-induced neuropathic pain
Authors: Malon Jennifer T , Cao Ling 
Published: January 2023

Abstract
Our previous studies have indicated that both microglial CD40 and spinal cord infiltrating CD4+ T cells play critical roles in the maintenance of peripheral nerve injury-induced neuropathic pain using a murine model of neuropathic pain, spinal nerve L5 transection (L5Tx). It is well accepted that chemokines play important role in the development of neuropathic pain. To further understand the role of microglial CD40 and CD4+ T cells in peripheral nerve injury-induced spinal cord chemokine response, we determined the levels of various chemokines in the lumbar spinal cord in CD40 knockout (KO), CD4 KO, and wild type (WT) BALB/c mice post-L5Tx. Using a multiplex assay, a total of eight chemokines CXCL1 (KC), CCL1 (TCA-3), CCL2 (MCP-1), CCL3 (MIP-1 alpha), CCL5 (RANTES), CCL11 (Eotaxin), CCL17 (TARC), and CCL22 (MDC) were examined. In WT mice, but not KO mice, L5Tx induced significant, gradual increases in CCL2, CCL3 and CCL5 up to day 21 post-L5Tx. At RNA level, L5Tx induced less pronounced increases of these chemokines in both types of KO mice compared to WT mice. These reduced chemokine response correlate with our previous observation that both CD40 KO and CD4 KO mice displayed significantly less mechanical hypersensitivity following L5Tx. Interestingly, L5Tx induced a significant increase in CXCL1 only in CD40 KO mice. Intrathecal injection of CXCL1 significantly reduced L5Tx-induced mechanical hypersensitivity in WT mice, indicating a potential protective effect of CXCL1 in neuropathic pain. Altogether, our data suggest chemokines’ roles in the development of neuropathic pain are chemokine type-specific.
NOD1 ligand administration restores optimal steady-state hematopoiesis in germ-free mice
Authors: Iwamura Chiaki , Jankovic Dragana , Bouladoux Nicolas , Belkaid Yasmine , Sher Alan 
Published: January 2023

Abstract
The microbiota is required for optimal hematopoiesis. When compared to specific-pathogen free (SPF) mice, germ free (GF) animals display decreased numbers of hematopoietic stem cells (HSC), common myeloid progenitors (CMP) and common lymphoid progenitors (CLP) in bone marrow. Muropeptides produced by both gram-negative and gram-positive bacteria are important agonists of the innate immune response and are recognized by the intracellular pattern-recognition receptors NOD1 and NOD2. In the present study, we examined both direct and indirect effects of NOD signaling on hematopoietic homeostasis. While stimulation with NOD1 or NOD2 ligands had no effect on survival/proliferation of HSC, CMP and CLP in vitro, exposure of bone marrow-derived stroma cells (BMSC) to NOD1, but not NOD2, ligand induced expression of the differentiation factors SCF, IL-7, IL-3, Thpo and IL-6. Interestingly LPS, which is known to act directly on hematopoietic precursors, selectively induced only IL-6 in BMSC. To test the effects of NOD1 ligand in vivo, we compared groups of GF animals with and without peroral NOD1 ligand administration. NOD1 ligand treatment restored to normal levels serum concentrations of SCF, Thpo and IL-6, as well as the numbers of HSC, CMP and CLP in bone marrow. Taken together, these findings demonstrate that NOD1 ligand induces BMSC to produce cytokines that regulate the size of the major hematopoietic precursor pools. Thus, NOD1 signaling appears to be a major factor underlying the requirement for the microbiota in the maintenance of steady-state hematopoiesis.
This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious diseases.
Compromised emergency hematopoiesis in obesity requires TLR4
Authors: Borghesi Lisa A , Liu Ailing , Ding Ying 
Published: January 2023

Abstract
Following acute injury/infection, bone marrow (BM) precursors must responsively redirect from steady-state to emergency hematopoiesis. Prospective and retrospective studies establish obesity as risk factor for infection but the mechanisms are poorly understood. Here, we show in a murine model of obesity that moderate changes in steady-state BM hematopoiesis become exaggerated during hematopoietic duress. At steady-state, diet-induced obese mice have a 30% decrease in BM hematopoietic stem cells (HSCs) with a parallel increase in splenic HSCs. HSCs are functionally competent in vitro and following competitive transfer in vivo. BM lymphoid and myeloid progenitors in obese mice are numerically intact but the transcriptional profiles and differentiation potential are strikingly myeloid-biased, accompanied by myeloid skewing of peripheral blood. Responses to acute hematopoietic challenge are deficient. Emergency hematopoiesis following chemotherapeutic ablation is reduced 60% in obesity. Likewise, emergency myelopoiesis in response to endotoxin is characterized by accumulation of immature rather than mature myeloid cells in obese mice. The obesity-associated inflammatory environment plays a key role as transfer of obese BM to lean recipients restores emergency immune response to chemotherapeutic challenge. Moreover, mice deficient in toll-like receptor 4 (TLR4), a central regulator of inflammation, retain robust hematopoietic rebound responses despite diet-associated weight gain. Thus, in obesity, moderate changes in steady-state blood cell production mask major defects in hematopoietic stress responses, via a TLR4-dependent mechanism.
Ubiquitylation of the Paf oncoprotein and interaction with PCNA is essential for hematopoietic stem cell function and development.
Authors: Shettigar Megha , Savic Miloje , Sant’Angelo Derek B , Denzin Lisa K 
Published: January 2023

Abstract
Hematopoietic stem cells (HSCs) are critical for the lifelong production and maintenance of all blood cell types. The molecular mechanisms that guide this process remain poorly understood. The 15kDa proliferating cell nuclear antigen (PCNA) associated factor (Paf) is a potent oncogene that is over-expressed in most cancers. We have previously shown that Paf is essential for HSC and progenitor function and development. Paf deficient mice (Paf−/−) are leukopenic due to reduced number of HSCs and committed progenitors. Paf−/− HSCs failed to maintain quiescence, to self-renew and to support long term hematopoietic reconstitution. To determine the in vivo molecular interactions and pathways by which Paf functions to mediate hematopoiesis, we introduced mutant versions of Paf into the Paf−/− mice. These unique mouse models allowed us to show that Paf-PCNA interactions and Paf ubiquitylation are both essential for hematopoiesis. Furthermore, biochemical analyses of cells from these mice showed that Paf interaction with PCNA was essential for nuclear localization and proper ubiquitylation of Paf. Collectively, therefore, our studies show that Paf function is dependent upon the ability to interact with PCNA and that the ubiquitylation of Paf regulates Paf’s function during hematopoiesis. Analyses are ongoing to further delineate the molecular mechanism by which Paf mediates HSC function and development.