bluuebunny/crossref_metadata_2025_split huggingface dataset:
IKKβ in recipient myeloid cells promotes lung allograft acceptance and prevents the accumulation of intragraft IL-17+ CD4+ T cells (169.33)
Authors: Huang Howard , Yamamoto Sumiharu , Sugimoto Seiichiro , Zhu Jihong , Krupnick Alexander , Kreisel Daniel , Gelman Andrew 
Published: January 2023

Abstract
Background Mechanisms linking acute solid organ injury to rejection are poorly understood. We previously reported maintenance of IKKβ activity in recipient myeloid cells protects lung grafts from acute injury. We now ask if recipient myeloid cell IKKβ activity regulates lung allograft survival. Methods Balb/c lungs were transplanted into B6 recipients carrying A) Myeloid-specific IKKβ deletion (IKKβΔMye) or B) floxed IKKβ alleles (IKKβfl/fl). Post-surgery, recipients were immunosuppressed (IS) with MR1/anti-CD40L and CTLA4-Ig. In a second cohort, IS-IKKβΔMye and IS-IKKβfl/fl recipients were also treated with control Ig, IL-23p19 or IL-17-specific Abs. Lung allografts were analyzed on POD7 for histopathology and accumulation of IFNγ+ and IL-17+ T cells by FACS analysis. Results Acute rejection occurred in IS-IKKβΔMye, but not IS-IKKβfl/fl recipients. Moreover, IS-IKKβΔMye recipients developed marked intragraft accumulation of IFNγ+CD4+, IFNγ+CD8+ and IL-17+CD4+ T cells. IS-IKKβΔMye recipients treated with IL-23p19 Abs accepted their lungs and had fewer intragraft IL-17+CD4+ T cells with little change in IFNγ+CD4+ and IFNγ+CD8+ T cell abundance. By contrast, IL-17 Ab treatment depleted intragraft IL17+CD4+ T cells, but led to expansion of intragraft Th1 cells and did not prevent rejection. Conclusions IKKβ-regulated signals in recipient myeloid cells couple acute lung graft injury to alloimmunity by preventing Th17-mediated rejection in a IL-23p19-dependent manner.
Crucial roles of mast cells in the development of a murine model of polymyositis (171.20)
Authors: Yokota Masaya , Suzuki Kotaro , Nakagomi Daiki , Tokoyoda Koji , Nakayama Toshinori , Kohsaka Hitoshi , Iwamoto Itsuo , Nakajima Hiroshi 
Published: January 2023

Abstract
Objective: In addition to a pivotal role of mast cells in allergic diseases, recent data suggest that mast cells play a crucial role in a variety of immune responses. However, their role in the pathogenesis of autoimmune skeletal muscle diseases has not been clarified despite their distribution in skeletal muscle. Therefore, the objective of this study is to determine the role of mast cells in the development of a murine model of polymyositis, C protein-induced myositis (CIM). Methods: The susceptibility of mast cell-deficient WBB6F1-KitW/KitWv mice (W/Wv mice) to CIM was compared with that of wild-type (WT) mice. The effect of mast cell reconstitution with bone marrow-derived mast cells (BMMCs) on the susceptibility of W/Wv mice to CIM was also evaluated. Results: W/Wv mice exhibited significantly reduced disease incidence and histological scores of CIM as compared with WT mice. The infiltration of macrophages but not of CD8+ T cells in the skeletal muscle was attenuated in CIM of W/Wv mice. The expression of monocyte chemotactic protein-1 (MCP-1) in skeletal muscle was reduced in W/Wv mice. Vascular permeability in skeletal muscle was elevated in WT mice but not in W/Wv mice upon CIM induction. Engraftment of BMMCs restored the incidence and histological scores of CIM in W/Wv mice. Conclusion: Mast cells play critical roles in the development of CIM.
Non-invasive imaging of islet infiltration reveals an early window of CRIg-dependent diabetes determinism in NOD mice (171.29)
Authors: Fu Wenxian , Wojtkiewicz Gregory , Weissleder Ralph , Benoist Christophe , Mathis Diane 
Published: January 2023

Abstract
All juvenile NOD mice exhibit insulitis, but there is substantial variation in progression to diabetes. We demonstrate that a patient-validated magnetic-resonance-imaging strategy to non-invasively visualize local effects of pancreatic-islet inflammation can predict diabetes onset in NOD mice. MRI signals acquired during a narrow early time-window allowed pre-sorting into disease-progressors and -nonprogressors and an estimate of time-to-diabetes. We exploited this capability to identify novel elements correlated with disease protection. Highlighted was CRIg (complement receptor of the immunoglobulin superfamily), which tagged a subset of macrophages associated with diabetes resistance. Administration of CRIg-Fc to young NODs depressed MRI signals and diabetes incidence. Besides nominating new regulators of disease progression, this study demonstrated that diabetes is set at an early age in NOD mice.
IL-23 induces IRF5 and polarizes inflammatory M1 macrophages to promote inflammation in a mouse model of arthritis (171.5)
Authors: Li Hao , Hsu Hui-Chen , Li Jun , Yang PingAr , Wu Qi , Cua Daniel , Oukka Mohamed , Mountz John 
Published: January 2023

Abstract
Increased numbers of macrophages (MΦs) is an early hallmark of active arthritis. Expression of IL-23R has been identified on myeloid cells. We determined if IL-23 can regulate the pathogenesis of collagen II-induced arthritis (CIA) by directly modulating development of MΦs. AdIL-17 was injected to Il23p19-/- and Il23p19+/+ mice to induce equal levels of IL-17 yet Il23p19-/-mice were more resistant to CIA compared to Il23p19+/+ mice. Dramatic expansion of IL-23R+ MΦs, which are the major producers of IL-6 and TNFα in the draining LN of mice with CIA, occurred only in Il23p19+/+ but not Il23p19-/- mice. IL-23 suppressed the expression of anti-inflammatory TGFβ and IL-10 produced by M2 MΦs and promoted expression of inflammatory IL-6 and TNFα produced by M1 MΦs in vitro. IL-23 prevents the ability of M-CSF to promote development of anti-inflammatory M2 MΦs by inducing the expression of Irf5, an M1 specific transcription factor. Using GFP-Foxp3 reporter mice, accumulation of Foxp3+ Tregs were only observed in Il23p19-/- but not Il23p19+/+ mice with CIA. Coculture of IL-23 stimulated MΦs with naïve CD4 T cells prevented the development and function of Treg cells, which could be reversed in the presence of anti-IL-6. Our results suggest that IL-23 induces the expression of IRF5 and promotes M1 MΦs that perpetuate the development of CIA. One important function of IL-23-activated MΦs was to prevent the development of Treg cells via an IL-6 dependent mechanism.
Up-Regulation of Stromal Cell-Derived Factor by IL-17 and IL-18 via Phosphatidylinositol 3-Kinase Dependent Pathway (171.8)
Authors: Cho Mila , Lee Seon-Yeong , Park Jin-Sil , Oh Hye-Joa , Son Hye-Jin , Ryu Jun-Geol , Kim Ho-Youn 
Published: January 2023

Abstract
IL-17 producing Th17 has a key role in the pathogenesis of autoimmune inflammation. Among various cytokines which are interwoven with the IL-17 pathway, members of IL-1beta family including IL-18 have recently gained significance. In the present study, we stimulated synovial fibroblasts with the combination of IL-17 and IL-18, and quantified the cellular production of stromal cell-derived factor-1 (SDF-1) with ELISA and its mRNA with RT-PCR. Both IL-17 and IL-18 significantly increased the level of SDF-1, not only individually but also synergistically (p&lt;0.05). The synergism was effectively suppressed by anti-IL-17, anti-IL-18 antibodies and PI3K inhibitor. In conclusion, PI3K-dependent synergism between IL-18 and IL-17 is first observed in this study, and adds a novel perspective for the role of IL-18 in immune regulation. The two cytokines’ individual effects, mutual interaction and synergism draw a crisscrossing map between IL-1 family and IL-17.
Natural Regulatory T Cell Controls Physiological Tolerance And Regional Immune Privilege: Studies on (C57BL/6xA/J) F1 (B6AF1) DEREG (“depletion of regulatory T cell”) Mice (171.9)
Authors: Harakal Jessica , Rival Claudia , Qiao Hui , Sampson Robert , Tan Steven , Cho Yumee , Sparwasser Timothy , Tung Kenneth 
Published: January 2023

Abstract
Although CD4+CD25+ Foxp3+ regulatory T cell (Treg) prevents autoimmune disease, its depletion in normal mice does not cause organ-specific autoimmunity, thus Treg’s physiological role in tolerance remains unclear. Different outcomes after Treg depletion in two models of Diphtheria toxin (DT) receptor-Foxp3 adult B6 mice have been reported: scurfy syndrome versus no effect. Herein, we report autoimmune disease of testis, ovary, stomach and lacrimal gland in the DEREG B6AF1 mice after Treg depletion. Male B6AF1 DEREG mice show massive immune complex and complement deposition, defective blood-testis barrier, and loss of sperm production. Importantly, immune injury is preceded by defective testis immune privilege, which also occurs reversibly in B6 DEREG mice that lack testis-specific autoAb. AutoAb in male B6AF1 DEREG mice target germ cells but also antigen common to steroidogenic testis (Leydig) cells and ovarian cells. In fact, male CD4 T cells adoptively transfer both orchitis and oophoritis; and autoAb of female B6AF1 DEREG mice with oophoritis targets a different ovarian Ag: the zona pellucida. These findings indicate gender-specific tolerance mechanisms. Notably, the Abs and gonadal failure are part of the human autoimmune polyendocrine syndrome (APS), some with autoimmune regulator (AIRE) gene mutations. Therefore, natural Treg control physiological systemic and regional tolerance to major gonadal Ag and Treg deficiency could explain APS and AIRE-related autoimmunity.
OCT-1 acts as a repressor of C-reactive protein gene expression (172.13)
Authors: Hammond David , Thirumalai Avinash , Voleti Bhavya , Zhang Shuang , Agrawal Alok 
Published: January 2023

Abstract
C-reactive protein (CRP), an ancient host-defense plasma protein, is produced by hepatocytes. In Hep3B cells, CRP expression is induced by IL-6; IL-1β synergistically enhances the IL-6 effect. A critical regulatory segment on the CRP promoter contains binding sites for transcription factors C/EBPβ (-48 to -57) and NF-κB (-63 to -74). The κB site overlaps an octamer motif (-59 to -66) which is the binding site for the constitutively expressed transcription factor OCT-1. OCT-1 is known to function both as a transcriptional repressor and activator depending upon the promoter context. The aim of this study was to investigate the function of OCT-1 on the CRP promoter. In luciferase transactivation assays, overexpressed OCT-1 inhibited cytokine-induced CRP expression. EMSA, mutational analysis of the κB site, and the OCT-1 dose-response assays suggested that OCT-1 and NF-κB compete for binding to their overlapping cognate sites. Deletion of the OCT-1 site drastically reduced the cytokine response because the κB site was altered as a consequence of deleting the OCT-1 site. Surprisingly, overexpressed OCT-1 inhibited the residual cytokine-induced CRP expression through the promoter lacking the OCT-1 site. OCT-1 also inhibited overexpressed C/EBPβ-induced CRP expression. We conclude that OCT-1 acts as a repressor of CRP gene expression and it does so by occupying its cognate site on the promoter and also via other transcription factors by an as yet undefined mechanism.
IL-33 retains mast cells in a selectively unresponsive state to bacterial cell wall products (172.15)
Authors: Sandig Hilary , Jobbings Cath , Orinska Zane , Bulfone-Paus Silvia 
Published: January 2023

Abstract
Mast cells are located at sites of microbial entry into the host therefore it is important that their response to pathogen associated molecular patterns (PAMPs) is tightly regulated to avoid unnecessary activation and pathology. Here we show that treatment of mast cells with picomolar concentrations of the stromal cell product IL-33 renders the cells insensitive to bacterial cell wall products. Responsiveness to antigen, cytoplasmic dsDNA and TLR7/8 agonists is unaffected or enhanced by IL-33. The IL-33 induced selective tolerance is dependent on the IL-33 receptor ST2 and independent of c-kit. The LPS insensitivity cannot be explained by up-regulation of the TLR4 signalling inhibitors A20 or Tollip nor does IL-33 affect the levels of TLR4, MyD88 or TIRAP, rather the cytokine potently causes rapid IRAK1 degradation which is sustained for at least 24 h. Unlike its redundant role in macrophages, we show that IRAK1 is a key component of TLR4 signalling in mast cells. LPS treatment also resulted in down-regulation of IRAK1 protein levels which may explain the mechanism behind endotoxin tolerance in mast cells. We propose a hitherto unidentified role for IL-33 in maintaining immune homeostasis by retaining mast cells in a selectively responsive state.
IL-33 is processed into mature bioactive forms by neutrophil serine proteases (172.26)
Authors: Lefrançais Emma , Roga Stéphane , Gautier Violette , Gonzales de Peredo Anne , Monsarrat Bernard , Girard Jean Philippe , Cayrol Corinne 
Published: January 2023

Abstract
IL-33 is a chromatin-associated nuclear cytokine from the IL-1 family, which has been linked to many inflammatory diseases. IL-33 signals through the receptor ST2 and drives production of cytokines in innate effector cells and T helper type 2 lymphocytes. IL-33 is constitutively expressed in the nuclei of endothelial cells and in epithelial cells of tissues exposed to the environment. It was initially believed that IL-33, like IL-1β and IL-18, requires processing by caspase-1 for biological activity. On the contrary, we reported that full length IL-33 is biologically active, and that processing by apoptotic caspases results in IL-33 inactivation, rather than activation. We also found that full length IL-33 is released upon cellular damage and we proposed that IL-33 may function, similarly to HMGB1, as an endogenous danger signal. Because IL-33 plays important roles in inflammatory diseases, we hypothesized that IL-33 could be cleaved by proteases released during inflammation. We analyzed the effects of inflammatory proteases from innate effector cells, on IL-33 processing and biological activity. We found that IL-33 can be cleaved and activated by several inflammatory proteases. Interestingly, all forms generated by these proteases are “super-active” IL-33 forms that contain an intact IL1-like cytokine domain. We propose that the inflammatory microenvironment exacerbates disease-associated functions of IL-33 through the generation of “super-active” IL-33 forms.
Calcium/Calmodulin-Dependent Protein Kinase Kinase 2 Regulates Macrophage-Mediated Inflammatory Responses (172.35)
Authors: Racioppi Luigi , Noeldner Pamela , Lin Fumin , Arvai Stephanie , Means Anthony 
Published: January 2023

Abstract
Calcium/calmodulin-dependent Kinase Kinase 2 (CaMKK2) plays a key role in regulating food intake and energy expenditure at least in part by its actions in hypothalamic neurons. Previously we showed that loss of CaMKK2 protected mice from high fat diet (HFD)-induced obesity and glucose intolerance. However, whereas pair-feeding HFD to WT mice to match food consumption of CAMKK2-null mice slowed weight gain, it failed to protect from glucose intolerance. Here we show that relative to WT mice, HFD-fed CaMKK2-null mice are protected from inflammation in adipose and remain glucose tolerant. Moreover, loss of CaMKK2 also protected mice from endotoxin shock and fulminant hepatitis. We explored the expression of CaMKK2 in immune cells, and found it to be restricted to those of the monocyte/macrophage lineage. CaMKK2-null macrophages exhibited a remarkable deficiency to spread, phagocytize bacteria and synthesize cytokines in response to the Toll Like Receptor 4 (TLR4) agonist lipopolysaccharide (LPS). Mechanistically, loss of CaMKK2 uncoupled the TLR4 cascade from activation of protein tyrosine kinase 2 (PYK2; also known as PTK2B). Our findings uncover an important function for CaMKK2 in mediating mechanisms that control the amplitude of macrophage inflammatory responses to excess nutrients or pathogen derivatives.
Altered humoral immune responses in mice deficient for the Fc receptor for IgM (FcμR) (172.37)
Authors: Honjo Kazuhito , Kubagawa Yoshiki , Jones Dewitt , Dizon Brian , Ohno Hiroshi , Kearney John , Kubagawa Hiromi 
Published: January 2023

Abstract
Unlike humans, FcμR expression in mice is restricted to B cells with a hierarchy of cell surface expression level: follicular &gt; marginal zone (MZ) &gt; newly formed in spleen and B-2 = B-1a &gt; B-1b in peritoneal cavity. To define the in vivo function of FcμR, Fcmr-deficient (KO) mice were generated by gene targeting. While total splenic CD19+ B and CD3+ T cell-numbers were comparable in KO and littermate control (WT) mice, MZ B cells were reduced ~4 fold and B-1 cells were increased ~2 fold in KO as compared with WT mice. Both serum IgM and IgG3 antibody (Ab) levels in naïve animals were significantly elevated in KO than WT mice. IgM and IgG3 natural Abs reacting with the nucleus or cytoplasm of HEp-2 cells were also elevated in KO mice. When immunized i.p. with a live avirulent strain of S. pneumoniae (R36A), much more robust and long-lasting IgM, IgG3 and IgA Ab-responses to phosphorylcholine developed in KO at low doses of R36A compared with WT. By contrast, when immunized i.p. with nitrophenyl (NP)-coupled chicken γ-globulin in alum, primary IgM anti-NP responses were comparable in both groups of mice, but secondary IgM responses were significantly impaired in KO mice. In contrast, the primary IgG1 anti-NP responses were impaired in KO, however secondary IgG1 responses were indistinguishable in both KO and WT mice irrespective of the antigen dose. These results show that Fcmr ablation results in altered Ab responses to both T-independent and -dependent antigens.
γδ T Cells and diet-induced inflammation in adipose tissue (173.2)
Authors: Mehta Pooja , Smith C. Wayne 
Published: January 2023

Abstract
Adipose tissues contain several subsets of immune cells. Relatively little is known about their contributions to adipose tissue inflammation induced by feeding mice a diet rich in saturated fats. Using a model of diet-induced obesity in male C57BL/6J mice, we investigated the possible contributions of γδ T cells to this inflammation. γδ T cells make up about one-third of the total T cell population in the epididymal adipose tissue. The γδ T cell receptor was blocked in wild-type mice using an anti-TCRδ antibody. A decrease in macrophage marker F4/80 was observed in these mice as compared to saline-treated control mice on high fat diet (HFD). TCRδ-/- mice adipose tissue failed to show an increase in mRNA expression of cytokines such as CCL-2, IL-6, IFN- γ even though they ate similar amounts of food and showed similar weight gain pattern as wild-type mice. A fraction of adipose tissue γδ T cells were shown to produce IFN-γ in obese mice by flow cytometry and were CD27+, a marker for IFN-γ-producing γδ T cells in the periphery. Obesity also results in inflammation in the skeletal muscle and liver, along with adipose tissue inflammation. Obese TCRδ-/- mice have reduced expression of markers of inflammation in the muscle after 5 weeks on HFD and liver after 6 months on HFD as compared to wild-type mice. These results are consistent with the conclusion that adipose tissue, liver and skeletal muscle inflammation during high saturated fat feeding is dependent in part on γδ T cells.
Opsonizing antibodies against influenza virus proteins mediate activation of plasmacytoid dendritic cells and are broadly cross-reactive. (P6194)
Authors: Ricklin Meret , Zimmer Gert , Summerfield Artur 
Published: January 2023

Abstract
Cross-protective immunity are observed between different strains of influenza viruses within one subtype and even between certain subtypes in the absence of neutralizing antibodies. So far most studies have focused on T cell immunity as the main mechanism of heterologous protection. The aim of this study was to test and characterize the functional and cross-reactive activity of antibodies against nucleoprotein (NP), hemagglutinin (HA) and neuraminidase (NA) of swine influenza viruses in the pig model. Our results demonstrate that antibodies against the internal well-conserved NP of distant strains can mediate NP-RNA complex uptake by plasmacytoid DC resulting in a robust IFN-alpha response. This function can mainly be observed at low concentrations of NP-RNA complexes released from dying infected cells. Furthermore, antibodies against the external HA and NA can mediate efficient uptake of immune complexed virus resulting in a robust IFN-alpha response at low concentrations of virus and antibodies. This reactivity is found with both, neutralizing and non-neutralizing antibodies. The latter are highly cross-reactive within on subtype and even between subtypes. In addition to T-cell immunity, such antibodies could play a role in promoting subtype cross-reactive (partial) immunity after influenza virus infection or following vaccination. Studies to test the impact of opsonizing antibodies in vivo are ongoing.
mTOR regulates protection against a lethal H5N1 influenza infection by modulating the antibody response (P6184)
Authors: McGargill Maureen , Keating Rachael , Hertz Tomer , Lukens John , Wehenkel Marie , Harris Tarsha , Edwards Benjamin , McClaren Jennifer , Brown Scott , Surman Sherri , Wilson Zachary , Hurwitz Julia , Chi Hongbo , Doherty Peter , Thomas Paul 
Published: January 2023

Abstract
Highly pathogenic H5N1 avian influenza A viruses pose a serious threat for global catastrophe. Due to frequent mutations in the influenza genome, current vaccination protocols promote only strain-specific responses, and therefore fail to provide protection against novel pandemic strains. Antibodies that protect against multiple subtypes of influenza have been identified, however, these antibodies are extremely rare, and the immunological mechanisms that lead to their development are not clear. We show here that rapamycin, an immunosuppressive drug that inhibits mTOR, promoted cross-strain protection against lethal H5N1 infection when administered during H3N2 vaccination. Surprisingly, this protection did not require memory CD8 T cells, but rather required CD4 T cells and B cells, suggesting the protection was antibody-mediated. In support of this, serum from rapamycin-treated mice immunized with a H3N2 strain protected naïve mice from a lethal H5N1 infection. Our data further reveal that rapamycin reduced germinal center formation and B cell class-switching, yielding a unique repertoire of antibodies that was more protective against a lethal, heterosubtypic influenza infection. These data not only reveal a requirement for mTOR in B cell class-switching, but also indicate that a broader antibody repertoire, which provides better protection against multiple strains of influenza, can be achieved by reducing germinal center formation during the primary infection.