bluuebunny/crossref_metadata_2025_split huggingface dataset:
WNT signaling programs the development of IL-17 producing γδ T cells and Innate Lymphoid Cells (115.17)
Authors: Malhotra Nidhi , Narayan Kavitha , Sylvia Katelyn , Melichar Heather , Kang Joonsoo 
Published: January 2023

Abstract
IL-17/IL-22 producing γδ T cells and other innate lymphoid cell (ILC) subsets safeguards the mucosal epithelia of oral, reproductive, respiratory and intestinal tracts against infection and damages. γδ T cell subsets originate in the thymus and are exported as pre-made effectors, while the other ILC effector subsets differentiate in the gut associated lymphoid tissues. Whether a common gene network program distinct from that operating in adaptive T cells controls IL-17/IL-22 production in all innate lymphoid effectors is unknown. We demonstrate that sry high mobility group (HMG) box transcription factors (TFs), SOX13 and other family members, function in a positive loop to control the intrathymic differentiation of IL-17 producing γδ T cells. In contrast, another HMG TF TCF1, the nuclear effector of canonical WNT signaling, is the primary negative regulator of the network. Furthermore, we show that TCF1 is also required for the functional differentiation of ILCs. Together, the results suggest the existence of a TF network that controls all innate IL-17 producing effectors, independent of tissue origin and T cell antigen receptor expression, distinct from that involved in generating IL-17 producing adaptive T cells.
IFNbeta-1b alters the composition of circulating B cell subsets, and leads to changes in the B cell cytokine secretion profile in patients with relapsing-remitting multiple sclerosis. (116.9)
Authors: Mielcarz Daniel , Bergeron Alan , DeLong John , Smith Kathleen , Heyn Alexandra , Mack Karen , Conrad Mary Ann , Oliver Brant , Kasper Lloyd , Channon Jacqueline 
Published: January 2023

Abstract
Recent studies provide strong evidence for a role for B cells in the pathology of RRMS. In order to explore the effect of IFNbeta-1b treatment on B cell phenotype and function in RRMS patients, blood was drawn from 10 RRMS patients before treatment and again 2 and 6 months after daily injections of IFNbeta-1b. Cryopreserved PBMCs were thawed and stained with panels of antibodies against B cell surface antigens. At baseline, RRMS patients have increased frequencies of naïve CD19+CD20+ B cells and decreased frequencies of memory B cells when compared with age-matched healthy controls. CpG-stimulated PBMCs from patients treated with IFNbeta-1b show an increase in IL-10 production and a decrease in IL-6 production by naïve, memory and B1 cells (a recently-described subset of autoantibody producing cells that are CD20+CD27+CD43+). These changes in cytokine production are indicative of a change from a pro- to an anti-inflammatory phenotype. In addition, this treatment alters the composition of circulating B cell subsets, leading to an increase after six months in circulating naïve B cells and a decrease in both memory and B1 cells, both cell types of which are potentially pathogenic in RRMS. Although the number of subjects in this study was limited, these findings suggest that alterations in B cell phenotype and function may be a mechanism by which IFNbeta-1b reduces disease activity.
Short chain fatty acids induce IL-1β production: The role of monocarboxylate transporters (MCTs) (117.16)
Authors: Mirmonsef Paria , Makinde Hadijat , Zheng Justin , Spear Greg 
Published: January 2023

Abstract
Short chain fatty acids (SCFAs) are products of anaerobic bacteria at mucosal sites, such as the female genital tract in bacterial vaginosis (BV). IL-1β, a potent proinflammatory cytokine, is found at elevated levels in the vaginal fluids of BV+ women. We recently found that SCFAs induce IL-1β in monocytes. Here, we tested whether SCFAs could control IL-1β production by either: 1) inducing pro IL-1β in the cytoplasm, and/or 2) causing inflammasome activation and release of IL-1β by acting as a “second” danger signal. We found that exposing peripheral blood mononuclear cells (PBMCs) for 24-hours to physiological levels of either acetic or butyric acid resulted in a modest increase in IL-1β levels in vitro. The release of IL-1β was more robust and occurred more rapidly when PBMCs were treated with SCFAs first, followed by exogenous ATP as a “danger” signal. SCFAs themselves were not potent danger signals as they failed to increase the release of LPS-induced pro IL-1β. Since SCFAs can enter cells via MCTs, we blocked these transporters using pharmacological agents and found that MCTs were necessary for SCFA-mediated IL-1β production. These findings show that SCFAs can induce cytoplasmic pro IL-1β production and that their effects are MCT-dependent. Because IL-1β is an important proinflammatory mediator, these results enhance our understanding of how SCFAs may contribute to the inflammatory environment seen in BV.
TLR4 senses proteinase activity to mediate allergic lung disease and macrophage fungistatic response. (117.18)
Authors: Ongeri Valentine , Byrd Tiara , Kheradmand Farrah , Corry David 
Published: January 2023

Abstract
Asthma is characterized by the presence of T-helper type 2 (Th2) cells in the lung. Our lab has shown that active fungal proteinases are requisite for robust Th2 cell generation and allergic airway inflammation that protects against fungal invasion during airway infection. Macrophages (MΦs) interact with inhaled pathogens and control airway infections via toll like receptors (TLRs) which may play a role in host defense against inhaled fungi. We hypothesized that fungal proteinases activate one or more TLRs in MΦs resulting in allergic lung disease and highly efficient fungal killing. Wildtype mice and mice deficient in specific TLRs (TLR4) and their adaptor molecules (MyD88-/- and TRIF-/- mice) were intranasally infected with viable conidia of Aspergillus niger and assessed for the asthma phenotype. Bone marrow cells were also harvested from TLR4-/- and wildtype mice to assess for differentiation of MΦs via RNA expression of canonical markers and cultured with the viable conidia to determine their effect on fungal growth.TLR4-/- mice failed to develop asthma-like disease while MyD88-/- and TRIF-/- mice had normal or exaggerated responses. Fungal proteinase induced differentiation of naive MΦs that profoundly inhibited fungal growth in vitro in a TLR4 dependent manner. Our findings therefore suggest a “Biased Agonism” model of TLR4 signaling in which distinct ligands may activate alternative signaling pathways that give rise to entirely different immune responses.
The generation of M2 monocytes in cultures of human peripheral blood mononuclear cells exposed to 137Cs γ-rays (117.2)
Authors: Nakamura Kiwamu , Okita Yamato , Cornforth Michael , Kobayashi Makiko , Suzuki Fujio 
Published: January 2023

Abstract
Thermally injured patients who are carriers of M2MΦ are greatly susceptible to various opportunistic infections. Since the similarly increased susceptibility to the infection is seen in patients with irradiated injuries, in this study we investigated the effect of 137Cs γ-irradiation on the M2MΦ generation in cultures of human peripheral blood mononuclear cells. Peripheral blood mononuclear cells (PBMC), isolated from healthy volunteers by Ficoll - Hypaque density gradient centrifugation, were exposed to 2 - 8 Gy of 137Cs γ-rays. CD14 positive monocytes were isolated from the irradiated PBMC using magnetic beads, and stimulated with Staphylococcus aureus Cowan strain (0.0075% SAC) for 24 hours. Culture fluids were harvested and analyzed for cytokines by ELISA. In the results, IL-10 was detected and IL-12 was not detected in the culture fluids of monocytes from 137Cs γ-irradiated PBMC, while IL-12 was detected and IL-10 was not detected in the culture fluids of healthy donor monocytes. Also, CCL1 was detected and CXCL13/CCL17 were not detected in the culture fluids of monocytes isolated from 137Cs γ-irradiated PBMC, while all of these chemokines were not produced by healthy donor monocytes. These results suggest that patients with irradiated injuries may be carriers of M2b monocytes.
Pregnane X receptor dependent TLR4 expression regulates innate immune response to intracellular bacteria (117.25)
Authors: Qiu Zhijuan , Schouten Jonathan , Mukherjee Subhajit , Acharya Nandini , Maher Leigh , Salazar Juan , Cervantes Jorge , Mani Sridhar , Khanna Kamal 
Published: January 2023

Abstract
The Pregnane X receptor (PXR) is a member of the nuclear receptor family, which is highly expressed in liver as well as in intestine and regulates the transcription of genes involved in the metabolism, transport and elimination of xenobiotics. Recently, the role of PXR and xenobiotic metabolism in regulating inflammation has become evident. Here we demonstrate that in addition to its role in xenosensing and drug metabolism, PXR signaling is also essential for mediating innate antimicrobial immune responses. Mice lacking PXR were highly susceptible to the intracellular bacteria Listeria Monocytogenes (LM). Bone marrow derived macrophages (BMDMs) from PXR-/- mice were proficient in internalizing bacteria, but incapable of clearing LM. Surprisingly, the over activation of Toll-like receptor 4 (TLR4) signaling in the absence of PXR was the singular determinant of susceptibility in PXR-/- mice since mice that were deficient in both PXR and TLR4 were efficient in clearing LM. Furthermore, administration of TLR4 specific inhibitors rescued the ability of PXR-/- mice and BMDMs to clear bacteria. Our results demonstrate an unexpected role of PXR in controlling innate immunity by negatively regulating TLR4 gene expression. In addition, our study has uncovered a remarkable impact of TLR4 signaling in driving the quality of antimicrobial immune response to gram-positive bacteria.
The defensive role of interferon-γ-producing immature myeloid cells in severe invasive group A Streptococcus infections (118.7)
Authors: Matsumura Takayuki , Ikebe Tadayoshi , Ohnishi Makoto , Watanabe Haruo , Kobayashi Kazuo , Ato Manabu 
Published: January 2023

Abstract
Streptococcus pyogenes (group A Streptococcus; GAS) is one of the most versatile bacteria among human pathogens. Non-invasive GAS infections can cause common diseases, such as pharyngitis and impetigo. Whereas, severe invasive GAS infections can lead to rapid progressive and life-threatening manifestations, including sepsis, necrotizing fasciitis, and streptococcal toxic shock syndrome (STSS). Although GAS-derived superantigens activate T cells to release excessive amounts of cytokines which are considered to participate in the pathogenesis of STSS following severe invasive GAS infections, it remains unclear which factors are protective against such infections and which cell population is the source of them. Here we show that mice infected with severe invasive GAS isolates, but not with non-invasive GAS isolates, exhibit high concentrations of plasma interferon (IFN)-γ during the early stage of infection. IFN-γ is necessary to protect mice, and is produced by a novel population of granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent immature myeloid cells with ring-shaped nuclei (IFN-γ-producing immature myeloid cells; γIMCs). These γIMCs express monocyte and granulocyte markers, and also produce nitric oxide. The adoptive transfer of γIMCs ameliorates infection in wild-type and IFN-γ-deficient mice. Our results indicate that γIMCs have a defensive role during the early stage of severe invasive GAS infections.
Glucocorticoid induced leucine zipper mimic inhibits experimental autoimmune encephalomyelitis (119.7)
Authors: Srinivasan Mythily , Srihari Janardhanam 
Published: January 2023

Abstract
Multiple sclerosis (MS) is a relapsing remitting neurological disease mediated by inflammatory cell infiltration in the brain and spinal cord followed by demyelination. The profound anti-inflammatory activity and the ability promote peripheral deletion of activated lymphocytes make glucocorticoids (GCs) the preferred agents in the management of relapse. The therapeutic efficacy of GCs is largely attributed to the inhibition of nuclear factor-κB (NF-κB), the master regulator of inflammatory responses. Peptides from different subunits of NF-κB complex have been shown to suppress inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Here, we report a novel strategy to selectively target activated NF-κB and regulate inflammation. Glucocorticoid induced leucine zipper (GILZ) is a recently described molecule transcriptionally upregulated by GCs. GILZ binds to and inhibits the nuclear translocation of NF-κB thereby suppressing transactivation of inflammatory mediators. This suggests that the anti-inflammatory activity of GCs can be attributed to the inducible upregulation of GILZ. Rationally designed GILZ-mimic protects mice against relapsing remitting EAE. Mechanistically treatment with GILZ-mimic suppresses nuclear translocation of p65, inhibits Th1 specific transcription factor T-bet and upregulates Th2 transcription factor GATA-3. In conclusion, our results suggest that the GILZ: p65 interaction is a potential target for multiple sclerosis.
Effects of low doses of allergen administration and/or probiotics supplementation on cow’s milk protein allergy in a mouse model. (120.10)
Authors: Thang Cin , Boye Joyce , Zhao Xin 
Published: January 2023

Abstract
Cow’s milk allergy (CMA) is one of the most common food allergies among infants and children of developed countries. Accumulating evidence indicates that probiotic supplementation and oral tolerance (OT) induction have food allergy reducing properties. However, there is no report regarding the effects of small doses of allergen and/or multi-strains probiotics (VSL#3) supplementation on CMA. In this study, we examined the effects of OT induction by low doses of allergen and/or VSL#3 supplementation on CMA in a mouse model. Mice were intraperitoneally sensitized and then orally challenged with β-lactoglobulin (BLG), one of the major milk proteins. Allergic responses, including hypersensitivity scores, sera immunoglobulins, fecal IgA and cytokines from spleen lysates, were monitored. Compared to BLG-sensitized control mice, mice supplemented with VSL#3 and/or administered with low doses of allergen showed significantly lowered hypersensitivity scores and reduced BLG-specific serum IgE levels. Allergy reducing effects of VSL#3 supplementation was associated with significantly higher levels of fecal IgA while suppression of both Th-1 and Th-2 responses were observed in OT-induced mice. However, mice that received both low doses of allergen and VSL#3 exhibited allergen-specific protection at the systemic level and the potential to protect non-specific challenges at the mucosal level through increased total intestinal IgA.
Regulation of expression of SLAMF4 on the surface of mucosal lymphocytes (120.13)
Authors: Liao Gongxian , Song Joo-Hye , O’Keeffe Micahel , Calpe Silvia , Castro Wilson , Magelky Erica , Wang Ninghai , Mora Rodrigo , Reinecker Hans-Christian , Terhorst Cox 
Published: January 2023

Abstract
SLAMF4 is a cell surface receptor, which is primarily known as a regulator of cytotoxicity and cytokine secretion by mouse NK cells upon engagement with its counter-structure CD48. Here, we found SLAMF4 is highly expressed on the surface of most mucosal CD8+ T cells, whereas it is only expressed on some CD44+ CD8+ splenic cells. Upon transfer of naïve SLAMF4− CD8+ T cells derived from Thy1.2+ B6 mice into Thy1.2− B6, donor cells were found to express SLAMF4 after entry into the mucosa. The increase in SLAMF4+ CD8+ cells was due to upregulation of the receptor gene rather than to expansion of a small subset of memory CD8+ T cells. Consistent with the high level of IL-15 in the intestinal mucosa and its requirement for the maintenance of memory CD8+ T cells, we found that recombinant IL-15 induces SLAMF4, particularly the short isoform of SLAMF4, expression on CD8+ T cells. Costimulation with αSLAMF4 significantly increased the αCD3ϵ-induced infiltration of CD8+ T cells in small intestine and exacerbated the inflammation in the small intestine of IL-10-IRES-GFP reporter mouse. As control, αSLAMF4 alone did not cause inflammation in the intestine. In conclusion, the differential expression on mucosal CD8+ T cells as well as the dual nature of SLAMF4 function suggests that SLAMF4 might be involved in regulating the fine balance between the maintenance of tolerance and immune surveillance in the intestinal mucosa.
The role of Platelet Factor 4 in local and remote tissue damage in a mouse model of mesenteric ischemia/reperfusion injury (120.18)
Authors: Ioannou Antonis , Lapchak Peter , Rani Poonam , Lieberman Linda , Yoshiya Kazuhisa , Kannan Lakshmi , Dalle Lucca Jurandir , Kowalska Anna , Tsokos George 
Published: January 2023

Abstract
The robust inflammatory response that takes place during ischemia reperfusion injury (IR/I) recruits factors from both the innate and adaptive immune system. However the contribution of platelets and their products such as Platelet Factor 4 (PF4; CXCL4), during the pathogenesis of IR/I has not been thoroughly investigated. We show that a deficiency in PF4 protects mice from local and remote tissue damage after 30 minutes of mesenteric ischemia and 3 hours of reperfusion in PF4-/- mice compared to control B6 mice. This protection was independent from Ig or complement deposition in the tissues. However, neutrophil and monocyte infiltration was decreased in the lungs of PF4-/- mice compared with B6 control mice. Platelet-depleted B6 mice transfused with platelets from PF4-/- mice displayed reduced tissue damage compared with controls. In contrast, transfusion of B6 platelets into platelet depleted PF4-/- mice reconstituted damage in both intestine and lung tissue. We also show that PF4 may modulate the release of IgA. Interestingly, we show that PF4 expression on intestinal epithelial cells is increased after ischemia/reperfusion at both the mRNA and protein levels. In conclusion, these findings demonstrate that PF4 represents an important mediator of local and remote tissue damage.
Knockout of mitogen-activated protein kinase phosphatase (Mkp)-1 exacerbates colitis development in interleukin-10-deficient mice (120.21)
Authors: Liu Yusen , Matta Ranyia , Barnard John , Wancket Lyn , Yan Jing , Grieves Jessica , Frazier W. Joshua , Nelin Leif , Cato Andrew 
Published: January 2023

Abstract
Il-10-/- mice develop colitis associated with exaggerated Th1/Th17 responses. Mkp-1 is a negative regulator of MAPKs, and its expression is enhanced by IL-10. To understand the role of Mkp-1 in the regulation of mucosal immune responses, we studied the effect of Mkp-1 deletion on the pathogenesis of colitis in Il-10-/- mice. We found that deletion of Mkp-1 on an Il-10-/- background accelerated the development of colitis. Il-10-/- mice exhibited a mild intestinal inflammation in the SPF environment, and rectal prolapse rarely appeared before 6 months. In contrast, majority of the Mkp-1-/-/Il-10-/- mice developed severe colitis rapidly and presented with rectal prolapse after 2-3 months. Colons of Mkp-1-/-/Il-10-/- mice showed diffuse transmural chronic inflammation and mucosal hyperplasia, with significant more proliferating crypt epithelial cells than those of Il-10-/- mice. Moreover, Mkp-1-/-/Il-10-/- mice also developed conjunctivitis and blepharitis. Large intestines of Mkp-1-/-/Il-10-/- mice contained significantly higher levels of pro-inflammatory cytokines, and exhibited greater p38 and ERK activities than did colons of Il-10-/- mice. Splenocytes and lymphocytes from Mkp-1-/-/Il-10-/- mice produced higher levels of Th1 cytokines ex vivo than did cells from Il-10-/- mice upon activation. Our studies support a pivotal role of Mkp-1 as a negative regulator in the mucosal immune responses and highlight its protective function against the development of IBD.
The role of the Rho-associated kinase ROCK in the differential regulation of CXCL8 and CCL2 production by Caco-2 epithelial cells. (120.23)
Authors: Perey Aaron , McGee Dennis 
Published: January 2023

Abstract
Two chemokines found at elevated levels in Inflammatory Bowel Disease (IBD), CXCL8 and CCL2, may play important roles in perpetuating the chronic inflammation that characterizes this condition. Interleukin-1 (IL-1) and Tumor Necrosis Factor-α (TNF-α), which have both been found at elevated levels in IBD, can stimulate the production of CXCL8 and CCL2 by Caco-2 epithelial cells. Previous results from our laboratory have shown that ROCK may be essential for optimal production of CXCL8, as suppression of ROCK activity with Y27632 suppressed IL-1 induced CXCL8 production. We now show that inhibiting ROCK also suppresses TNF-α induced CXCL8 mRNA and protein secretion similar to previously seen with IL-1. Furthermore, inhibiting ROCK suppressed TNF-induced phosphorylation of JNK, but had no effect on IκBα phosphorylation or degradation. Yet inhibition of ROCK actually resulted in significantly elevated levels of CCL2 mRNA with IL-1 and TNF stimulation, and TNF-induced CCL2 secretion was significantly increased while IL-1-induced CCL2 secretion was unchanged. These results suggest that ROCK does play a role in regulating chemokine production in intestinal epithelial cells, but in a very different manner for CXCL8 compared to CCL2. While the purpose of this differential regulation is unclear, it may be an important mechanism for modulating the influx of specific groups of inflammatory cells into affected tissues.
Small afferent nerve fibers control skin inflammation. (120.27)
Authors: Riol Lorena 
Published: January 2023

Abstract
Recent advances in the realm of the skin inflammation have made clear that diseases such as psoriasis or atopic dermatitis cannot be considered as purely immunological because cutaneous peripheral nerve fibers have been shown to play a role in both skin diseases. We have generated some exciting preliminary data in which we observed that local peripheral nerves regulate skin inflammation in animal models of psoriasis and atopic dermatitis (CHS). We have elucidated that in particular, small efferent nerve fibers play an important role in controlling the initiation and determining the magnitude of skin inflammation. Moreover, this effect occurs very promptly even before resident dendritic cells are activated and migrate to the skin-draining lymph nodes. We are currently elucidating the mechanisms by which small nerve fibers interact with the skin associated immune system which may lead to new therapeutic targets to treat skin inflammatory diseases such as psoriasis or atopic dermatitis.