bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism of formation of novel bone forming cells (monoosteophils) from LL-37 treated monocytes. (111.26)
Authors: Zhang Zhifang , Shively John 
Published: January 2023

Abstract
BACKGROUND: Bone generation and maintenance involve osteoblasts, osteoclasts, and osteocytes. However, an incomplete understanding of bone forming cells during wound healing has led to an unfilled clinical need such as nonunion of bone fractures. Recently, our published paper showed that LL-37, the active peptide of human cathelicidin, has an ability to induce monocyte differentiation to a new type of bone forming cells (monoosteophils). We now have investigated the mechanism of monoosteophil formation. RESULTS: Treatment of monocytes from blood with LL-37 for 6 days resulted in their differentiation to monoosteophils. Monoosteophil on osteologic discs built bone-like nodules which consist of calcium and phosphorus. Monoosteophils are identified by up-regulation of integrin a3 and a3b1 and down-regulation of CD14, CD16, CD32, and CD163 on the membrane. Microarry analyses indicated the differential expression of 206 genes in the formation of monoosteophils. Among these genes we found elevated level of CCL22. CONCLUSION: the present study demonstrated that integrin a3 and a3b1, CD14, CD16, CD32, and CD163 can be used as differentiation markers of monoosteophils and that the chemokine CCL22 may be involved in their formation.
Understanding the signaling kinetics that drive dendritic cell maturation (111.28)
Authors: Gonzalez-Lergier Joanna , Hartmann Boris , Sealfon Stuart 
Published: January 2023

Abstract
Dendritic cells are antigen-presenting cells responsible for the initiation of immunity. Immature DCs act as sentinels that, upon recognizing a pathogen, undergo a maturation process; the mature DCs then secrete signals to stimulate the appropriate immune response. Previous studies have shown that the cytokines that are produced by infected DCs during their maturation process can initiate a paracrine signaling program in naïve DCs that subsequently leads to a partial maturation of these cells thereby making them more capable of mounting an efficient response. Further combinatorial studies have shown that three cytokines (TNFα, IL-1β and IFNβ) are primarily responsible for this activation of naïve DCs, Consequently, there must be some convergence in the diverse signaling pathways initiated by these cytokines that is responsible for the syngergistic effect in DC maturation that has been observed. The phosphorylation and translocation profiles of signaling proteins and transcription factors downstream of these three cytokines are being used, in combination with measurements of maturation marker upregulation and ability to stimulate T cells, to built a PLS model in order to identify the key signaling pathways that are responsible to the partial maturation of these DCs. Further in-depth studies can then be carried out in order to identify more precisely the regulation that occurs in these cells that makes them more efficient in their professional-antigen presenting abilities.
Chronic morphine modulates actin polymerization leading to inhibition of Fc-gamma receptor mediated phagocytosis (111.29)
Authors: Ninkovic Jana , Roy Sabita 
Published: January 2023

Abstract
Morphine has been known to modulate innate immune functions, by inhibiting macrophage phagocytosis. However, mechanisms by which morphine inhibits macrophage phagocytic ability remain to be explained. Our results indicate that chronic morphine treatment in vitro and in vivo inhibited Fcγ receptor mediated phagocytosis in murine macrophages by inhibiting actin polymerization. Using fluorescence microscopy and fluorometry, we showed that chronic morphine treatment led to inhibition of actin polymerization resulting in impaired internalization of opsonized dextran beads. Chronic morphine treatment inhibited activation of Rac1-GTPase, therefore inhibiting formation of lamellipodia and membrane ruffling. Morphine’s inhibition of Rac1-GTPase activation was abolished in J774 macrophages transfected with constitutively active Rac1. In addition, chronic morphine treatment led to an increase in intracellular cAMP, which resulted in inhibition of actin polymerization through a PKA dependant pathway. DB-cAMP, by increasing intracellular cAMP, led to suppression of actin polymerization while H89 treatment induced inhibition of PKA and abolished morphine’s inhibitory effect implicating cAMP as the key effector in morphine’s modulation of actin. Together these data indicate that chronic morphine by increasing cAMP, activating PKA which inhibits Rac1 GTP-ase, leads to inhibition of actin polymerization and phagocytosis.
Human plasmacytoid dendritic cells express Dectin-1 as an immune regulatory receptor (111.32)
Authors: Joo HyeMee , Ni Ling , Li Xiao-Hua , Li Dapeng , Duluc Dorothee , Gannevat Julien , Morel Christine , Zurawski Sandra , Banchereau Jacques , Zurawski Gerard , Oh SangKon 
Published: January 2023

Abstract
Dectin-1 is expressed on myeloid-derived antigen-presenting cells and plays an important role in host immunity against microbial infections. We here demonstrate for the first time that human plasmacytoid dendritic cells (pDCs) express functional Dectin-1. Dectin-1 could deliver intracellular signals to activate pDCs through Syk. As results of activation, pDCs upregulated surface expression of HLA-DR and co-stimulatory molecules. However, pDCs expressed lower levels of CD80, CD86, and CCR7 compared to pDCs activated via TLR9. Signaling via Dectin-1 also induced pDCs to secrete cytokines (IL-6, IFNα, and TNFα) and chemokines (IL-1β, IP-10, IL-8, MIP-1α, and MIP-1β). Most notably, pDCs activated via Dectin-1 secreted greater amount of IL-1β than pDCs activated via TLR9. Dectin-1 stimulated pDCs selectively upregulated inflammation-related gene signatures. We further demonstrated that pDCs activated via Dectin-1 could polarize CD8+ T cells toward IL-10-producing regulatory CD8+ T cells. Activation of pDCs, but not mDCs, via Dectin-1 also resulted in enhanced Th2 type CD4+ T cell responses as well as B cell differentiation into plasmablasts, and this was partly dependent on IL-1β secreted from pDCs. Therefore, we conclude that Dectin-1 expressed on human pDCs possesses unique function to control host immune responses.
Phenelzine potentiates production of proinflammatory cytokines via the NF-κB pathway in LPS-activated microglia cells (112.11)
Authors: Kim Hyunseong , Chung Hwan-Suck , Shin Minkyu , Bae Hyunsu 
Published: January 2023

Abstract
Phenelzine is a potent monoamine oxidase (MAO) inhibitor that is widely used and has been shown to be clinically efficacious in patients with depression. It is also well known that nitric oxide (NO) synthase inhibitors show preclinical antidepressant-like properties, which suggests that NO is involved in the pathogenesis of depression. The purpose of this study was to determine if phenelzine affects the production of NO and tumor necrosis factor-alpha (TNF- α) in activated BV-2 microglia cells. Phenelzine increased the lipopolysaccharide (LPS)-induced expression of inducible nitric oxide synthase (iNOS), as well as the release of TNF- α and IL-6 in BV-2 microglia cells. It is also confirmed that phenelzine increased the levels of NO, TNF-α and IL-6 in LPS-activated primary microglia cells. Phenelzine increased nuclear translocation of NF-κB by phospholylation of IκB-α in LPS-activated microglia cells. Taken together, these findings suggest that high doses of phenelzine could aggravate inflammatory responses in microglia cells that are mediated by NO and TNF-α.
Beta 7 integrin is essential for the induction of oral tolerance (112.15)
Authors: Kadono Takafumi , Ohmatsu Hanako , Sato Shinichi 
Published: January 2023

Abstract
Oral tolerance is one of the hallmarks of intestinal immunity that induces systemic unresponsiveness to orally ingested antigens. Beta 7 integrin is known to mediate lymphocyte migration to gut-associated lymphoid tissues, especially Peyer’s patches. We assume that lack of beta 7 integrin might affect oral tolerance due to defective lymphocyte migration to intestinal tissues. When mice were intraperitoneally immunized with OVA following oral OVA administration, beta 7 integrin deficient mice showed defective oral tolerance measured by OVA-specific IgG and IgM antibody titers, numbers of OVA-specific antibody forming cells, and proliferative responses to OVA. Oral tolerance in L-selectin deficient mice was unimpaired. Moreover, beta 7 integrin/ L-selectin double deficient mice showed defective oral tolerance to a similar degree as beta 7 integrin deficient mice, suggesting no additive effect of L-selectin deficienty. We also measured cytokine secretion from splenocytes following oral tolerance induction and found that whereas IFN gamma secretion was decreased in wild-type mice, this reduction was abrogated in beta 7 deficient mice. These results demonstrate that beta 7 integrin is essential for oral tolerance.
SNX9 as a novel biomarker for chronic inflammation-induced immunosuppression: implications for cancer therapy (112.16)
Authors: Ish-Shalom Eliran , Baniyash Michal 
Published: January 2023

Abstract
Chronic inflammation is the cause for immunosuppression observed in human and mouse with developing tumors; myeloid derived suppressor cells (MDSCs) accumulate and induce T and NK cell dysfunction associated with z down-regulation. Moreover, we discovered that z chain could serve as a biomarker to evaluate the efficacy of a given therapy; whether the tumor regresses or reappears, based on the developing chronic inflammatory environment. Recently, we identified SNX9, which is also expressed in B cells, as an additional biomarker playing a role in a pathway different from that of the z chain, for evaluating the immune status under chronic inflammatory conditions. Using the mouse melanoma model system (B16-F10.9), we found that SNX9 expression was significantly decreased, correlating with the tumor induced inflammatory environment. Our results also identify down-regulation of SNX9 expression in additional pathologies characterized by chronic inflammation such as during autoimmune disorders and infectious diseases, which correlates with elevated levels of MDSCs. Moreover, 5FU chemotherapy treatment, led to the recovery of SNX9 expression levels by eliminating the MDSCs population, indicating that SNX9 down-regulation is a reversible phenomenon and reflects the host’s chronic inflammatory state and immune status. These results may lead to a well-controlled personalized treatment of cancer-bearing hosts’ immune status by combining measurements of both z and SNX9.
Vitamin E isoforms directly bind PKCα and differentially regulate PKCα activity. (112.8)
Authors: McCary Christine , Yoon Youngdae , Cho Wonhwa , Cook-Mills Joan 
Published: January 2023

Abstract
Tocopherol isoforms of vitamin E differentially regulate inflammation and vascular cell adhesion molecule (VCAM)-1 signaling during leukocyte transendothelial migration. During VCAM-1 signaling, tocopherols modulate oxidative activation of protein kinase Cα (PKCα). Although tocopherols are antioxidants, it is not known whether tocopherols also directly regulate PKCα; therefore, we determined whether α-tocopherol and γ-tocopherol directly regulate non-oxidative or oxidative activation of purified PKCα. In a non-oxidative environment, phosphatidylserine (PS)/calcium cofactor-induced PKCα activity was increased by γ-tocopherol but not by α-tocopherol. In contrast, PS-independent oxidative-activation of PKCα was inhibited by α-tocopherol and by 10-fold higher concentrations of γ-tocopherol. In binding studies, lipid vesicles containing α-tocopherol or γ-tocopherol increased binding to the C2 domain (the PS binding domain), but not the C1b domain, of PKCα. To determine direct binding of tocopherols to PKCα in the absence of other lipids, we measured binding of a fluorescent α-tocopherol (NBD-α-tocopherol) to PKCα. Consistent with vesicle binding studies, NBD-α-tocopherol and PS competed for binding to PKCα, indicating that α-tocopherol binds the C2 domain. In summary, α-tocopherol and γ-tocopherol bind the C2 domain of PKCα, but differentially regulate PKCα activity. Therefore, α-tocopherol and γ-tocopherol can function as agonists or antagonists at the C2 domain of PKCα.
Gads is required for the expansion phase of CD8+ T cell-mediated immunity, but not the memory phase (113.27)
Authors: Zhang Elizabeth Yan , Parker Brooks , Yankee Thomas 
Published: January 2023

Abstract
The Gads adaptor protein is critical for TCR-mediated Ca2+ mobilization. We investigated how Gads regulates CD8+ T cell-mediated immunity following infection with an intracellular pathogen. Naïve CD8+ T cells from Gads+/+ OT-I or Gads-/- OT-I mice were adoptively transferred into congenic wild-type mice that were subsequently infected with OVA-expressing Listeria monocytogenes. After infection, expression of the activation markers was impaired in Gads-/- cells. Analysis of the kinetics of the immune response to infection suggested that Gads was not required for the onset of proliferation of OVA-specific CD8+ T cells, but was required for the maximal expansion of them. These data from the infection experiment were in contrast to our in vitro data, which showed Gads-dependent signaling pathways accelerated the exit from G0 phase of the cell cycle. These differences suggest that the inflammatory environment of the infected animals overcomes the need for Gads at early time points. At the peak of the immune response, comparable percentages of Gads+/+ and Gads-/- cells could produce IFN-γ, suggesting Gads-/- cells were functional. We also found that Gads was not required for the differentiation of naïve CD8+ T cells into memory cells, but Gads-/- memory cells did not expand as well as Gads+/+ cells upon re-infection. We conclude that Gads regulates the expansion phase of the primary and secondary immune responses, but not the generation of memory CD8+ T cells following infection.
The licensing of natural killer cells (113.3)
Authors: Rytova Valeria , Takei Fumio , Jiang Boxiang 
Published: January 2023

Abstract
The interaction between inhibitory Ly49 receptors and MHCI is important for the functional maturation of NK cells, known as “NK cell licensing.” NK cells from MHCI-deficient β2microglobulin (β2m)-KO mice are not cytotoxic and cannot efficiently kill their targets, as they are not licensed. Our goal is to determine the mechanism through which β2m-KO NK cells are kept hyporesponsive to otherwise NK-sensitive targets. Comparison through cytotoxicity assays confirmed that ex-vivo NK cells from poly-IC-injected wild type (WT) mice kill the prototypic YAC1 target, whereas NK cells from β2m-KO mice do not. Interestingly, both express similar levels of granzyme B and adhere to immobilized ICAM-1, the ligand for LFA-1. Further, confocal analysis of NK cells interacting with YAC1 showed that WT NK cells aggregate and polarize lytic granules toward their targets, while β2m-KO NK cells are deficient in granule polarization. Once stimulated by plastic beads coated with ICAM-1, both WT and β2m-KO NK cells reorganize their actin cytoskeleton. Stimulation by beads coated with ICAM-1, H60 and CD48 (ligands for stimulatory NKG2D and 2B4 receptors), induces aggregation and polarization of lytic granules in WT but not in β2m-KO NK cells. This suggests that critical components of the cytotoxicity pathway generated by stimulatory receptor interactions are impaired in β2m-KO NK cells, preventing aggregation and polarization of cytotoxic granules, and the release of their contents towards targets.
Investigating the role of 4-1BB and 4-1BBL in dendritic cell immunobiology (113.6)
Authors: Mbanwi Achire , Lin Gloria , Watts Tania 
Published: January 2023

Abstract
The tumour necrosis factor (TNF) receptor family member 4-1BB, and its TNF family ligand, 4-1BBL, have been thoroughly investigated as potent modulators of the CD8 T cell response. During a viral infection, 4-1BBL on APC, binding to 4-1BB on activated T cells mediates survival signaling in activated and memory CD8 T cells. Similarly to T cells, 4-1BB is also induced on dendritic cells (DC) following activation; however, how 4-1BB and 4-1BBL modulate DC biology is poorly understood. We provide evidence that DC express both 4-1BB and 4-1BBL upon activation with a microbial stimulus in vitro, and that these molecules interact on maturing DC. Using an in vivo DC vaccination model, we demonstrate that in the absence of 4-1BBL on the DC, there is a 2-3 fold defect in the ability of these DC to generate influenza-specific CD8 T cells in a WT host. This defect is not observed when 4-1BB-/- hosts are vaccinated with WT DC, suggesting that 4-1BBL on the DC is not acting through 4-1BB in the host, but intrinsically on the DC. Even more striking is that 4-1BB-/- DC do not show this defect in the generation of flu-specific CD8 T cells, raising the possibility of a 4-1BB-independent 4-1BBL mechanism. In that regard, we further show that anti-4-1BBL antibodies can induce Erk activation in WT DC, but not in 4-1BBL-/- DC. These results identify 4-1BBL as a DC modulator and have overall implications for vaccine design.
High mobility group nucleosome-binding protein 1 acts as an alarmin critical for the induction of immune response (113.7)
Authors: Yang De , Postnikov Yuri , Li Yana , Tewary Poonam , de la Rosa Gonzalo , Kliman Dennis , Furusawa Takashi , Bustin Michael , Wei Feng , Oppenheim Joost 
Published: January 2023

Abstract
Alarmins, defined as endogenous mediator(s) capable of promoting the recruitment and activation of antigen-presenting cells (APCs) including dendritic cells (DCs), can potentially promote immunity, however, their essential contribution to the induction immune responses remain to be demonstrated. Here we report the identification of HMGN1 as a novel alarmin that is critical to the induction of antigen-specific immune response. HMGN1 induced DC maturation and recruitment of APCs and activated NF-κB and multiple MAPKs, in a MyD88-dependent manner. HMGN1 promoted antigen-specific immune response upon co-administration with an antigen. Furthermore, knockout of HMGN1 in mice greatly reduced antigen-specific antibody and T cell responses upon intraperitoneal immunization with an antigen using LPS as an adjuvant. The impaired ability of HMGN1 KO mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from non-leukocytes played a more critical role in the induction of antigen-specific antibody and T cell responses. Thus, HMGN1 acts as a novel alarmin critical for the induction of adaptive immune response.
IL17 autoregulatory system in vitro and in vivo in a mouse model of autoimmune and viral diseases (114.5)
Authors: Nagata Takako , Ghilardi Nico , Kolls Jay 
Published: January 2023

Abstract
In the IL17 family, IL17A and F are known to be primary players. Concanavalin A (Con A) induced hepatitis is a model of autoimmune and viral diseases. We reported the production of IL17A increases by more than two orders of magnitude and IL17F by more than one order in IL17 receptor (IL17R) KO, in vivo and in vitro, compared to wildtype (WT). We have also shown IL17F in vitro downregulates the level of IL17A and F in WT, but doesn’t significantly downregulate either in IL17R KO. Hence, IL17F appears to autoregulate through IL17R. Here, we examine if and how IL17A and F each contribute to this system, in vivo and in vitro, with IL17A KO and IL17F KO. Furthermore, their contributions to liver damage are quantitatively evaluated. Results: IL17F increased around 7-fold in IL17A KO compared to WT both in vitro and in vivo. IL17A levels were similar in IL17F KO and WT in vitro and in vivo. Overall, IL17A level in IL17R KO&gt;&gt;in IL17F KO=in WT and IL17F level in IL17R KO&gt;in IL17A KO&gt;in WT. ALT (alanine aminotransferase) was significantly lower in IL17A KO than in WT. IL17F KO showed similar level to WT. Conclusion: Both IL17A and F appear to autoregulate in vivo and in vitro. However, since IL17A binds IL17R more strongly than IL17F, IL17R would tend to be monopolized by IL17A in WT. This explains why IL17A level in IL17F KO was similar to WT. IL17A appears to be primarily responsible for Con A induced hepatic inflammation.
IL-17 — a novel adipose tissue cytokine with anti-adipogenic and pro-osteogenic properties (114.6)
Authors: Zuniga Luis , Shen Wen-Jun , Joyce-Shaikh Barbara , Pyatnova Ekaterina , Richards Andrew , Thom Colin , Andrade Sofia , Cua Daniel , Gaffen Sarah , Kraemer Fredric , Butcher Eugene 
Published: January 2023

Abstract
Inflammatory mediators have the potential to impact a surprising range of diseases, including obesity, obesity associated metabolic syndrome, and autoimmunity. Adipocyte development and their function in lipid storage and metabolism are regulated in a complex fashion by inflammatory cytokines. Although IL-17 appears to mediate inflammation-associated bone loss, studies indicate IL-17 also has important homeostatic roles in facilitating wound repair and promoting cell proliferation. Recent evidence indicates IL-17 has an anti-adipogenic role while at the same time having an unexpected osteoprotective role; however the mechanisms of IL-17 mediated osteoprotection are ill defined. We show IL-17 is expressed in adipose tissue by leukocytes and is upregulated in obese fat. IL-17 deficiency enhances diet-induced obesity in mice. IL-17 suppresses adipocyte differentiation from mouse derived 3T3-L1 preadipocytes in vitro, and inhibits expression of adipocyte genes. Surprisingly, IL-17R and IL-17 deficiency led to increased bone mineral density in vivo in the absence of inflammation, and IL-17 treatment led to increased osteoblastogenesis in vitro. Over expression of IL-17 inhibited diet-induced obesity while leading to a pro-osteogenic serum profile in mice. Our findings indicate IL-17 as a homeostatic, anti-adipogenic, pro-osteogenic cytokine, capable of inducing osteoblasts from multipotent progenitors, and establishes a potential role for IL-17 in the bone/fat axis.
IL-7 uniquely maintains Treg cells that reverse diabetes in NOD mice via integrin-β7-dependent localization (115.10)
Authors: Li Cheng-Rui , Deiro Mia , Godebu Elana , Bradley Linda 
Published: January 2023

Abstract
Type 1 diabetes (T1D) develops as a consequence of a progressive autoimmune response that destroys insulin-producing β-cells in pancreatic islets. Because of their role(s) in controlling immune responses, considerable effort has been directed towards resolving whether regulatory T cells (Tregs) offer a clinical treatment to restore tolerance in T1D. We previously reported that in vitro induced adaptive Treg cells (aTregs) can reverse T1D and persist as protective memory cells in the NOD mouse model. In the current study, we investigated mechanisms that regulate aTregs. We found that these FoxP3+ aTregs expressed high levels of the IL-7 receptor, IL-7Rα, without the high affinity receptor for IL-2, CD25, which is found on natural Tregs (nTregs). IL-7Rα expression was mirrored by the dependency of aTregs on IL-7 for survival. IL-10 and TGF-β, effector cytokines of aTregs, were not essential for their maintenance. Nevertheless, IL-10 modulated cytokine production by aTregs and TGF-β was critical for protection. Furthermore, the expression of integrin-β7 was required for aTregs to localize and thereby function in the pancreas. The distinct homeostatic regulation of aTregs independently of a response to IL-2, which is defective in T1D patients, suggests that these cells represent a translatable candidate to control the autoimmune response.