bluuebunny/crossref_metadata_2025_split huggingface dataset:
MiR-146a regulated IL-6 expression promotes monocyte proliferation in sepsis patients (117.22)
Authors: Zhou Juhua , Chaudhry Hina , Zhong Yin , Perkins Linda , McGuire Franklin , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Sepsis is a serious medical condition, which is characterized by a systemic inflammatory state induced by a known or suspected infection. Despite extensive basic research and clinical studies, the pathogenesis of sepsis is still poorly understood. In the current study, we found that total peripheral blood mononuclear cell counts increased significantly, however, lymphocytes including CD4+ and CD8+ T cells decreased significantly in sepsis patients. Further studies demonstrated that monocytes increased significantly in sepsis patients. Plasma levels of IL-6, IL-8 and MCP-1 dramatically increased, whereas plasma levels of RANTES significantly decreased in sepsis patients compared with normal controls. MiRNAs such as miR-143, miR-145, miR-146a, miR-181a, miR-182, miR-199a, miR-486 and miR-1308 were dysregulated in sepsis patients. Down-regulation of miR-146a may be responsible for the increased levels of IL-6 expression, and thus may promote monocyte proliferation in sepsis patients. These results suggest that the modulation of IL-6 expression by dysregulated miR-146a in the control of monocyte proliferation may have implications in the pathogenesis and treatment of sepsis.
Natural killer lytic-associated molecule is a component of macrophage phagosomes and contributes to bacterial killing (117.23)
Authors: Lawrence Donald , Kornbluth Jacki 
Published: January 2023

Abstract
Macrophages are a critically important component of the immune system. They are equipped with oxidative and non-oxidative mechanisms to kill pathogens that have been compartmentalized into phagosomes following phagocytosis. Ubiquitin, a small protein modifier that regulates protein degradation, has been found to play a role in macrophage bacterial killing. Natural killer lytic-associated molecule (NKLAM) is an E3 ubiquitin ligase expressed in macrophages and natural killer cells. We have shown that NKLAM expression in macrophages is enhanced by Toll-like receptor agonists and pro-inflammatory cytokines. Using bone marrow-derived macrophages from wild type (WT) and NKLAM-deficient mice we found the levels of phagocytosis and phagosome acidification to be similar; however, killing of E. coli by NKLAM-deficient macrophages is less than by WT macrophages. Using confocal immunofluorescence microscopy, we found that NKLAM is colocalized with ingested bacteria. In assays using IgG-opsonized latex beads as targets, we demonstrated that NKLAM is translocated to the phagosome early in the maturation process. In addition, the presence of NKLAM in the phagosome temporally coincides with increased levels of ubiquitin. Collectively, our data demonstrate that NKLAM is a novel component of macrophage phagosomes and that NKLAM is involved in macrophage bactericidal functions.
Type I interferon induces necroptosis in macrophages during Salmonella Typhimurium infection (117.8)
Authors: Sad Subash , Robinson Nirmal , Mccomb Scott , Krishnan Lakshmi 
Published: January 2023

Abstract
Salmonella typhimurium (ST) is a virulent pathogen that induces rapid host-fatality. We observed that host-survival was enhanced in the absence of IFN-I signalling. Cell-transfer experiments indicated that increased survival of IFN-IR-deficient mice was attributed to efficient control of ST by macrophages. While there was no impairment in inflammasome activation in IFN-IR-deficient macrophages they were highly resistant to ST-induced cell-death. Specific inhibition of receptor interacting protein kinase-1 (RIP-1), or knock-down of RIP-3 prevented the death of wild-type macrophages, implicating necroptosis as a mechanism of cell-death. Furthermore, RIP-3-deficient mice, lacking necroptosis, displayed reduced macrophage-death and enhanced control of ST in vivo. Finally, IFN-I signalling directly induced RIP-1 phosphorylation in macrophages. Thus, ST exploits IFN-I-signalling to activate necroptosis of macrophages and promote immune-evasion.
Eosinophil-mediated lung host defense against Pneumocystis murina (118.6)
Authors: Nelson Michael , Burg Ashley , Metz Allison , Werner Jessica , Dunaway Chad , Steele Chad 
Published: January 2023

Abstract
We have recently reported that Src TKO mice, which demonstrate augmented lung clearance of P. murina (PM) (Infect Immun, May 2009), have enhanced expression of alternative macrophage activation (M2a) markers and the M2a-associated chemokines CCL17 and CCL22 (J Immunol, February 2011). As CCL17 and CCL22 often drive the recruitment of eosinophils, we questioned their role in PM lung defense. PM infection resulted in significantly increased expression of eosinophil peroxidase (Epx) mRNA, which was further enhanced in mice with greater resistance to PM lung infection. We further observed PM-induced mRNA expression of Prg2, but not Ear1 or Ear2, in the lungs. GATA1 deficient mice, which have a selective deficiency in eosinophils, demonstrated impaired PM lung clearance. In turn, Epx and Prg2 mRNA expression was significantly lower in GATA1 deficient mice. Finally, bone marrow-derived eosinophils exhibited the capacity to kill PM in vitro. Collectively, our work supports a role for eosinophils in lung host defense against Pneumocystis.
Tolerization of diabetogenic CD4+ T cells by intranasal treatment with CTA1R7K-DD containing specific peptide through the induction of FoxP3+ Treg cells (119.10)
Authors: Cardell Susanna , Fahlén-Yrlid Linda , Mark Linda , Löfbom Linda , Lycke Nils 
Published: January 2023

Abstract
Type I diabetes (T1D) results from immune destruction of insulin producing β-cells in the pancreas islets. Diabetogenic CD4+ T cells are key cells in the autoimmune process. To achieve tolerization of diabetogenic CD4+ T cells would therefore be an important advancement in the development of treatments of T1D. We previously described that a mutated (R7K), enzyme killed, form of the cholera toxin A1 subunit based adjuvant CTA1-DD induces specific tolerance rather than enhancement of immunity. Intranasal (i n) treatment with CTA1R7K-DD containing a type II collagen peptide reduced in vitro recall responses to the peptide, and moreover, ameliorated collagen induced arthritis in mice. Here, we use CTA1R7K-DD to investigate tolerization of diabetogenic CD4+ T cells of the non-obese diabetic (NOD) mouse, exploring diabetogenic TCR transgenic BDC2.5 CD4+ T cells. I n treatment of BDC2.5 NOD mice with CTA1R7K-DD containing a peptide specific for the BDC2.5 TCR reduced proliferation and IFN-γ production to in vitro peptide stimulation. Transfer of CD4+ BDC2.5 T cells to NOD.scid mice results in T1D development in 80-100% of recipient mice. In contrast, recipients of cells from BDC2.5 NOD mice treated with the CTA1R7K-DD peptide construct remained healthy. The i n treatment resulted in systemic increase in the frequency of CD4+ BDC2.5 transgenic T cells expressing FoxP3, suggesting that CTA1R7K-peptide-DD induces specific CD4+ Treg cells preventing T1D development.
Targeting the immunoproteasome with the second generation proteasome inhibitor ONX 0914: effects on IFN-alpha-induced monocyte-derived dendritic cells (119.4)
Authors: Verbrugge Sue Ellen , Emal Diba , Al Marjon , Lougheed Sinead , Chan Elena , Kirk Christopher , Dijkmans Ben , Scheper Rik , de Gruijl Tanja 
Published: January 2023

Abstract
Proteasome inhibitors (PI) have been proposed as therapeutic agents for autoimmune diseases. Bortezomib (BTZ) is the first registered PI targeting both the constitutive and the immunoproteasome. However, given reported toxicities, its suitability for long term treatment of chronic inflammation should be exercised with caution. Conceptually, ONX 0914 (ONX), a second-generation PI that specifically targets the immunoproteasome, may cause fewer unwanted side effects. High circulating IFN-alpha levels in autoimmune patients have been linked to systemic dendritic cell (DC) maturation, which may support chronic inflammation. In this study we compared the ability of ONX vs BTZ to interfere with IFN-DC development and function. While at non-toxic concentrations ONX (100 nM) and BTZ (5 nM) hampered differentiation of both IFN-DC and the more conventional IL-4-DC from monocytes (based on loss of CD1a expression), IFN-DC were more profoundly affected by proteasome inhibition; 65% to 25% vs 65% to &lt;5% (median, n=8), respectively. ONX and BTZ equally hampered maturation of IFN-DC (25-30% reduction in CD83 expression) and suppressed (up to 2-fold) their ability to induce allogeneic T-cell proliferation. Finally, release of IL-6 by IFN-DC, but not by IL-4 DC, was suppressed 2-3 fold by both ONX and BTZ. Collectively, these observations suggest that ONX may be equally effective as BTZ in inhibiting inadvertent type-1 IFN-mediated DC activation during chronic inflammation.
IMO-8400, a novel TLR7, TLR8 and TLR9 antagonist, inhibits disease development in mouse models of psoriasis (119.8)
Authors: Jiang Weiwen , Zhu Fugang , Tang Jimmy , Kandimalla Ekambar , La Monica Nicola , Agrawal Sudhir 
Published: January 2023

Abstract
Toll-like receptors (TLR) are involved in the pathogenesis of numerous autoimmune diseases, including psoriasis. The role of TLR7 and TLR9 in psoriasis is well established and TLR8 may also contribute to this disease. Blocking the activation of these receptors through a TLR antagonist represents a novel approach to the treatment of psoriasis. We have developed IMO-8400, a synthetic DNA compound that inhibits TLR7-, TLR8-, and TLR9-mediated immune responses in cell-based assays. Additionally, following subcutaneous administration in non-human primates, it suppresses ex-vivo immune responses mediated through these receptors. IMO-8400 was evaluated in preclinical mouse models of psoriasis, induced by IL-23 cytokine or antimicrobial peptide LL-37. Psoriasis-like skin lesions were induced in the ear of C57BL/6 mice by intradermal injection of IL-23 or LL37. Injected mice were treated with subcutaneous administration of IMO-8400. Mice were euthanized at end of study and tissue samples were taken for histological examination. Increase in ear thickness was inhibited in a dose-dependent manner by treatment with IMO-8400. Reduction in epidermal hyperplasia and infiltrating leukocytes was observed in sample tissues. Treatment with IMO-8400 was associated with elevation of serum IL-10 levels. IMO-8400 can effectively suppress lesion development in these psoriasis models. IMO-8400 has potential as a novel agent for the treatment of psoriasis and other autoimmune diseases.
A Dual PIM 1/3 Kinase Inhibitor Demonstrates Efficacy in Murine Models of Lupus and Multiple Sclerosis (119.9)
Authors: Robinson John , Pheneger Jed , Patrice Lee , Wright Dale , Brown Suzy , Sullivan Francis , Davis Gregg 
Published: January 2023

Abstract
PIM kinases are a family of 3 intracellular serine/threonine kinases, and have been shown to be uniquely regulated at the level of expression rather than by upstream phosphorylation. The PIMs are STAT-induced proteins and function as a key signaling node downstream of multiple cytokine, growth factor and oncogene pathways. Here we report the in vivo efficacy in mice of a small molecule PIM kinase inhibitor, AR317, in NZB/NZW Lupus, MOG EAE, and relapsing remitting EAE models. AR317 is a selective and potent inhibitor of PIM-1 and PIM-3 kinases in both the enzyme (IC50 = 0.2 nM PIM-1 and 0.5 nM PIM-3) and cellular setting (EC50 = 21 nM). Administered orally twice daily at 3, 10, and 30 mg/kg to NZB/NZW mice, AR317 afforded dose-responsive improvements in proteinuria, with normalization to base line at 30 mg/kg. Improvements in disease indices were also observed including reductions in spleen and kidney weights, increase in hematocrit, decreases in lymphocyte and neutrophil counts. In a mouse SJL MOG (35-55) EAE model, AR317 (70 mg/kg, BID) produced a significant reduction in ataxia over the course of the study. When dosed in the SJL/J PLP(139-151) mouse model of relapsing remitting EAE, AR317 exhibited marked efficacy vs. ataxia, with reductions in cumulative relapse scores at both 30 mg/kg and 90 mg/kg. These data support the hypothesis that a small molecule PIM 1/3 kinase inhibitor may provide efficacy for patients suffering from lupus or multiple sclerosis.
β-Arrestin-1 deficiency protects mice from experimental colitis (120.16)
Authors: Lee Taehyung , Lee Eunhee , Raehtz Sandi , McCabe Laura R. , Parameswaran Narayanan 
Published: January 2023

Abstract
β-arrestin-1 (β-arr-1) is an intracellular scaffolding protein demonstrated to regulate a number of different receptor-mediated signaling pathways, including Toll-like receptors in immune cells. Based on our recent studies in the regulation of TLR signaling by β-arr-1, we tested the hypothesis that β-arr-1 plays an important role in the pathogenesis of inflammatory bowel disease (IBD). Our results demonstrate that β-arr-1 knockout (β-arr-1-/-) mice are protected from experimental colitis compared to WT mice as determined by body weight loss, clinical score, and colon length. Consistent with the phenotypic consequences, histological examination and myeloperoxidase activity in the colon revealed attenuated inflammatory cell infiltration in the β-arr-1-/-mice compared to WT mice. To further determine the mechanisms, we examined various cytokines implicated in the pathogenesis of colitis. Our results demonstrate that β-arr-1-/- mice are deficient in expression and secretion of IL-6 in the colon compared to the WT mice. Taken together, these results demonstrate that β-arr-1-dependent signaling plays an important role in the pathogenesis of colitis likely via IL-6 production and therefore provides a potential pharmacological target in the treatment of IBD.
The neuropeptides α-MSH and NPY differentially modulate phagocytosis by macrophages (120.24)
Authors: Phan Toan , Mylvaganam Hari , Taylor Andrew 
Published: January 2023

Abstract
The ocular microenvironment tightly regulates immunity to prevent inflammation. These anti-inflammatory mechanisms are partly mediated by immunomodulating neuropeptides. We previously found that alpha-melanocyte stimulating hormone (α-MSH) and Neuropeptide Y (NPY) together induce activation of myeloid suppressor-like macrophages. In this study, we examined the possibility that α-MSH and NPY also modulate phagocytosis by macrophages. The monocytic cell line RAW 246.7 was treated with α-MSH or NPY at 1 ng/ml each, a concentration produced by retinal cells in culture. The treated cells were feed florescent bioparticles of Gram(-) E. Coli or Gram(+) S. Aureus with or without opsonization. Also, tested was the formation of phagolysosomes using pH sensitive florescent E. Coli or S. Aureus bioparticles. Phagocytic activity was assayed by flow cytometry. The α-MSH and NPY treated macrophages were significantly suppressed in their capacity to phagocytize unopsonized E. coli; however, suppression of S. Aureus phagocytosis was limited to NPY treated macrophages. In addition, α-MSH/NPY co-treatment suppressed both phagocytosis and phagolysosome formation in the macrophages. There was no change in phagocytic activity if the bioparticles were opsonized with antibody or complement. Therefore, as α-MSH and NPY together induce suppressor macrophages within the ocular microenvironment, they also modulate in a stimulus-dependent manner phagocytic signals within the macrophages.
Signaling through the P2X7 receptor for ATP induces psoriasis-like inflammation in human skin (120.28)
Authors: Mathers Alicia , Killeen Meaghan , Ferris Laura , Falo Louis 
Published: January 2023

Abstract
Current therapeutics for psoriasis includes the use of systemic acting immuno-suppressive drugs; however, long-term effects of these treatments remain a concern. A better understanding of the mechanism(s) involved in psoriasis pathogenesis is highly relevant for developing refined therapeutics. However, the immunological processes that perpetuate psoriatic lesions, particularly factors that stimulate DCs to bias autoimmune Th17 responses, are not well known. It is likely that alarmins, such as ATP, play a pivotal role in the pathogenesis by positive-feedback inflammatory mechanisms that break immunological self-tolerance and perpetuate immune responses. We have demonstrated the presence of P2X7R, an ATP receptor, in lesional and non-lesional psoriatic skin, suggesting a principal difference in skin of psoriasis patients and not just a change due to inflammation. Mechanistically, utilizing human cutaneous models, we determined that signaling via P2X7R initiates psoriasis-like inflammation in skin by mechanisms that include innate immunity, DC17 differentiation, and the induction of Th17 biased responses. Furthermore, our results define a prospective role for P2X7R signaling in perpetuating psoriasis lesions by stimulating the mir-21/VEGF pathway. In conclusion, we have begun to describe a potential mechanism of psoriasis lesional formation in humans, which will contribute to understanding the pathogenesis of psoriasis and lead to the development of refined therapeutics.
TIM-1 mediates the induction of ozone-induced airway hyperreactivity through the recognition of apoptotic cells in the lung (120.33)
Authors: Kim Hye Young , Lee HyunHee , Chang Ya-Jen , Chaung Ya-Ting , Shore Stephanie , Freeman Gordon , DeKruyff Rosemarie , Umetsu Dale 
Published: January 2023

Abstract
Asthma is a heterogeneous inflammatory disease of the lungs that has multiple triggers, including air pollution. The mechanisms however, by which non-allergic triggers such as air pollution cause asthma are poorly understood. In a model of air pollution-induced asthma, we found that chronic exposure to ozone induced airway hyperreactivity (AHR), a cardinal feature of asthma, independently of adaptive immunity. The AHR induced by ozone was however, dependent on TIM-1, an important susceptibility gene for asthma and a receptor for phosphatidylserine (PtdSer), a marker of apoptotic cells. Moreover, ozone exposure caused apoptosis in airway epithelial cells, which triggerred AHR by activating TIM-1 expressing natural killer T (NKT) cells. These results demonstrate an important role for TIM-1 in asthma, in which AHR results from the activation of NKT cells sensing damaged/apoptotic airway epithelial cells through TIM-1. We thus define a novel innate pathway to experimental asthma that involves apoptosis and TIM-1, and that links airway injury to inflammation and AHR.
MyD88 Expression on Villin Inhibits Obesity in High Fat Diet Mice (120.5)
Authors: Chao Chen , Xiang Yufei , Wang Yipeng , Peng Jian , Hu Youjia , Tai Ningwen , Hoshi Namiko , Zhou Zhiguang , Medzhitov Ruslan , Wen Li 
Published: January 2023

Abstract
To investigate whether MyD88 in the gut epithelial brush border plays a role in obesity and metabolic syndrome, we studied a transgenic mouse line expressing MyD88 only in villi (VillinMyD88+/+MyD88-/- mice). In this study, we fed young male wild type B6 (n=8), MyD88-/-B6 (n=6) and VillinMyD88+/+MyD88-/-B6 mice (n=13) with high fat diet (HFD) for 16 weeks. We investigated the metabolic, immunological and gut bacteria profiles of these mice. We found that VillinMyD88+/+MyD88-/-B6 mice had lower body weight, net weight gain, food consumption, total body fat mass, and white adipose tissue weight compared to B6 and/or MyD88-/-B6 mice (P&lt;0.05). Glucose and insulin tolerance tests showed that VillinMyD88+/+MyD88-/-B6 mice were more insulin sensitive than B6 and MyD88-/- B6 mice (P&lt;0.05). Interestingly, white adipose tissue in VillinMyD88+/+MyD88-/-B6 mice harbored fewer B cells, Th17 cells and IL-6+ cells than B6 and/or MyD88-/-B6 mice (P&lt;0.05). Moreover, the number of CD103+CD8+ cells were lower in spleen, mesenteric lymph node, and Peyer Patches of VillinMyD88+/+MyD88-/- B6 mice (P&lt;0.05) compared with B6 and MyD88-/-B6 mice. Gut flora study showed that B6 mice had more Lactobacillus, while MyD88-/-B6 and VillinMyD88+/+MyD88-/-B6 mice had more Enterococcus. However, VillinMyD88+/+MyD88-/-B6 mice had a higher ratio of Gram+/Gram- than MyD88-/-B6 mice in faeces. Our data revealed a novel role of MyD88 in gut epithelial brush border, which affects obesity and metabolism.
An IKKβ-IL-17 axis fine-tunes Ab responses to sublingual immunization (120.7)
Authors: Jee Junbae , Bonnegarde-Bernard Astrid , Iwakura Yoichiro , Karin Michael , Cormet-Boyaka Estelle , Boyaka Prosper 
Published: January 2023

Abstract
The nature of immune cells recruited at the sites of antigen exposure and the cytokine microenvironment play a key role at shaping immune responses. Using a model sublingual vaccine with Bacillus anthracis edema toxin as an adjuvant, we show that alteration of IKKβ signaling in myeloid cells (IKKβΔMye) enhanced the magnitude of Ab and T cell responses, compared to control mice. While this model vaccine failed to induce S-IgA Abs in control mice, significant S-IgA Ab responses were induced in mucosal secretions of IKKβΔMye mice. We also established that the sublingual vaccine recruited lower numbers of CD11b+F4/80+Gr1high and CD11b+F4/80-Gr1high, but higher number of CD11b+F4/80+Gr1- cells in the sublingual tissues of IKKβΔMye mice. In contrast, higher numbers of CD11b+F4/80+Gr1high and CD11b+F4/80-Gr1high, but lower number of CD11b+F4/80+Gr1- cells were recruited in the sublingual tissues of control and IL-17A KO mice. Lack of IL-17A signaling did not affect the magnitude of Ab responses to the sublingual vaccine. However, the profile of B cell epitope responses was affected in IL-17A KO mice. Furthermore, CD11b+ cells isolated from IKKβΔMye mice assisted B cell-differentiation and induced production of IgA Abs by IL-17Rhigh B lymphocytes in vitro. Our results support the existence of an IKKβ-IL-17 axis for regulation of mucosal immunity and identify IKKβ signaling as a potential target for improving induction of mucosal immunity by sublingual vaccines.
Full-length Interleukin-33 modulates the effects of Interleukin-4 in the lungs in vivo (120.8)
Authors: Kopach Pavel , Lockatell Virginia , Kang Phillip , Pickering Edward , Atamas Sergei , Luzina Irina 
Published: January 2023

Abstract
Previous reports have been inconsistent on whether Interleukin (IL)-33 necessarily promotes Th2 effects in vivo. This diversity of findings may be due to post-synthetic processing of IL-33. We compared the in vivo effects of full-length mouse (flm) and mature mouse (mm) IL-33 utilizing replication-deficient adenovirus (AdV)-mediated gene delivery. mmIL-33 promoted pulmonary eosinophilia, neutrophilia, and significant elevations in IL-4, IL-5, and IL-13 compared to AdV-NULL-infected controls (p &lt; 0.05 in all cases), whereas flmIL-33 had no such effects. A possibility was considered that flmIL-33 may modulate the effects of a prototypic Th2 cytokine, IL-4. The effects of AdV-mediated gene delivery of IL-4 were compared with the effects of combined flmIL-33 and mIL-4. In the latter case, a bicistronic AdV construct encoding flmIL-33 and mIL-4 was used to ensure co-localization of expression of both cytokines. On day 7 after instillation of the viral particles, IL-4-expressing mice had elevated eosinophils and neutrophils in their BAL, and animals expressing both flmIL-33 and IL-4 had yet significantly more BAL eosinophils and neutrophils compared with IL-4-expressing mice (p &lt; 0.05). Similar potentiating effects of flmIL-33 were observed on IL-4-driven increases in pulmonary cytokines TNF-α, IL-5, IL-13, MCP-1, and in goblet cell hyperplasia. These results suggest that although full-length IL-33 has no independent pro-Th2 effect on the lung, it potentiates such effects of IL-4.