bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytokine production during neonatal Escherichia coli sepsis drives disease severity through pathogen-specific pathways
Authors: Muske Josey , Knoop Kathryn 
Published: November 2024

Abstract
Late-onset neonatal sepsis (LOS) – often resulting from the dissemination of E. coli from the gut into the bloodstream – has an inverse correlation between severity and gestational age. In our previous data, we observed multiple E. coli strains - both pathogenic and commensal - were able to translocate from the gut and circulate systemically, resulting in variations of disease outcomes. It is unknown how the translocated E. coli strains can cause cytokine storm, lethality, and LOS, while similar E. coli is unable to cause such reaction. Additionally, we sought to understand how the neonatal immune response to sepsis is unique from that of older pups. We infected pups on either postnatal day 5-7 or 17-20 with a single-organism infection of pathogenic or commensal E. coli. During pathogenic E. coli infection, neonatal mice had increased cytokine levels, bacterial burden, and mortality, with contributions from IL-6 and TLR4 signaling, compared to periweaning mice. During co-culture with pathogenic E. coli, RAW-Blue cells produced more IL-6, similar TNFα, and less IL-1β compared to the commensal strain. The distinct difference in cytokine production suggests differential signaling by a pathogenic-specific pathway to cause lethality, cytokine production, and bacterial burden, specifically in neonates.
Discovery of clinical candidate GS8-164, a highly potent oral NLRP3 inflammasome inhibitor for inflammation disorders
Authors: Lv Yue , He Weiming , Zhai Wenqiang , Xia Yuanfeng , Yang Fanglong 
Published: November 2024

Abstract
The NLRP3 inflammasome is a component of the innate immune system that plays a crucial role in the pathophysiology of multiple metabolic diseases. But so far, no marketed drugs specifically targeting NLRP3 have been approved. Here, we report the characterization of GS8-164, a potent and selective NLRP3 inflammasome inhibitor with a new phthalazine skeleton. In vitro, GS8-164 displayed potent inhibition of IL-1b production in THP-1, human PBMC and human whole blood assays without inhibiting either IL-6 or TNF-α. In vivo, GS8-164 strongly inhibited production of IL-1β in an acute mouse peritonitis model, and attenuated pathological progress and production of IL-1β in a rat acute pericarditis model. GS8-164 has a good ADME and toxicology profile. In 14-day rat and dog toxicology studies, GS8-164 displayed good tolerance, excellent PK profile and a good safety window (&gt;50 fold). GS8-164 is under IND-enabling study and the clinical development is planned towards early 2025.
Infection-suppressed surfactant protein C alters alveolar type 2 cell lineage
Authors: Jain Krishan , Ji Hong Long , Zhao Runzhen 
Published: November 2024

Abstract
Suppressed surfactant protein C is a hallmark of respiratory infections. Acute Respiratory Distress Syndrome (ARDS) is a critical condition in pneumonia, COVID-19, and sepsis and involves damaged epithelial lining, cytokine storms, and lung edema. Alveolar type 2 (AT2) epithelial cells are stem cells of the distal lung and are vital for lung repair. AT2 cells secrete surfactant protein C which protects alveoli from collapse and infections. Whether downregulated SP-C affects the re-alveolarization via regulating AT2 fate remains unclear. We used alveolar organoids to compare AT2 lineages in wild-type (wt), sftpc gene mutated L184Q mice, and disrupted sftpc gene (KO) mice. H1N1 infection reduced AT2 cells in KO mice. Sftpc deficiency led to fewer AT2 cells and reduced organoid counts and organoid colony-forming efficiency in KO mice compared to wt controls. Confocal images and western blotting indicated increased AT1 differentiation in sftpc-disrupted organoids. Similarly, L184Q mice also exhibited reduced AT2 yield, organoid count, and organoid formation efficiency. Further, scRNAseq identified differentially expressed genes in sftpc-deficient AT2 cells. This study demonstrated that sftpc could be essential to regulate alveolar regeneration by modulating AT2 lineage. Suppressed surfactant protein C in infected lungs could be a potential druggable target for ARDS and COVID-19.
Weight cycling alters the immune composition of reproductive tissues, worsening infertility in female mice
Authors: Kalev-Altman Rotem , Hamilton Riley , Martinez-Navarrete Wenceslao , Guha Ray Aleepta , Wiseman Destini , Weinstock Ada 
Published: November 2024

Abstract
Obesity increases the risk of several comorbidities, such as infertility. While weight loss is highly recommended, maintaining a normal weight is typically unsuccessful, leading to weight regain (WR), which exacerbates inflammation and worsens comorbidities, compared to maintaining stable obesity, with reasons unknown. Hence, understanding the deleterious effects of WR holds great potential for decreasing the burden of metabolic diseases as well as infertility. Here, we hypothesized that WR has an adverse effect on female fertility compared to stable obesity. Females were fed high-fat diet for 14wks to establish obesity, then subjected to weight loss by reducing food intake by 30% for 2wks, followed by 3wks of free access to food to induce WR. Controls were age-matched mice that were freely fed high-fat diet without weight cycling. Females were assessed for immune composition of reproductive tissues or outcomes of mating with lean males. WR females showed lower pregnancy rate, smaller litter size and higher dystocia prevalence, resulting in in-uterus death of the fetuses, as compared to non-cycling females. Moreover, the uterus myometrium showed lipid accumulation only in WR females, suggesting a mechanism by which the fatty myometrium cannot contract properly leading to dystocia. In conclusion, weight cycling exacerbates obesity-related infertility. Further histology and flow cytometry analysis will determine whether and how immune cells in reproductive tissues are involved.
Adenosine analogs have immunomodulatory antiviral properties through the Adenosine A2A Receptor pathway
Authors: King Brionna , Huang Zhi , Hewins Peter , Cook Thomasina , Mirzalieva Oygul , Larter Kristina , Wyczechowska Dorota , Crabtree Judy , Garai Jones , Li Li , Zabaleta Jovanny , Barbier Mallory , Del Valle Luis , Jurado Kellie , Miele Lucio , Monticone Giulia 
Published: November 2024

Abstract
The COVID-19 pandemic has unveiled an urgent need for novel antivirals to control emerging infectious diseases. Classic antivirals are often insufficient to clear infections in the absence of an effective immune response. Immunotherapy could complement the use of antivirals; however, its application to infectious diseases remains largely unexplored. Adenosine analogs (AAs) are antiviral drugs which resemble the structure of adenosine, a metabolite which suppresses the immune response through activation of the Adenosine A2A Receptor (A2AR) in immune cells. We hypothesized that selected AAs have previously unrecognized immunomodulatory properties by acting as A2AR antagonists. In this study, we used molecular docking modeling to screen AAs for their capacity to bind to A2AR and test AAs for immunomodulatory properties in cell-based and in vivo assays. We found that selected AAs restored T-cell functions from adenosine-mediated immunosuppression in T-cells, suggesting that they are endowed with immunomodulatory properties through A2AR antagonism, in addition to their intrinsic antiviral properties. These immunomodulatory functions contribute to the antiviral activity of the AAs as we found that the analogs could restore antiviral T-cell responses in COVID-19 models. In conclusion, selected AAs could be used as novel dual – immunomodulatory and intrinsic – antiviral drugs and could represent effective therapies against emerging viral diseases and future pandemics.
Dysregulation of fetal-derived cochlear resident tissue macrophage mediate CMV-associated sensorineural hearing loss
Authors: Otsuka Kelly , Trujillo Emilio , Stout Jordan , Kfoury Peter , Park Albert , Beaudin Anna 
Published: November 2024

Abstract
Cytomegalovirus (CMV) is the most common congenital viral infection in the developed world and leading cause of non-genetic sensorineural hearing loss (SNHL) in children. Here we investigated the role of fetal-derived resident tissue macrophages (RTMs) in normal cochlear development and their role in CMV-associated SNHL.
Using genetic fate mapping, we uncovered dual sources of fetal-derived RTMs from yolk sac (YS) and fetal liver (FL) hematopoiesis. YS-derived RTMs naturally recede after cochlea maturity while FL-derived RTMs expand, revealing a temporal layering of RTMs. Additionally YS-derived and FL-derived RTMs demonstrate spatial specificity, seeding distinct cochlear tissues. Both anti-CSF1R depletion of fetal-RTMs and embryonic genetic deletion of YS-derived RTMs by CSF1R-flox lead to SNHL and impaired cochlear tissue development, revealing the requirement for fetal RTMs in normal cochlear development.
During CMV infection, scRNAseq and fate-mapping analysis revealed an infiltration of bone marrow-derived macrophages at the expense of yolk-sac derived RTMs, indicating that CMV infection disrupted the normal temporal layering of fetal-derived RTMs in the cochlea. Fetal-derived RTMs also upregulated inflammation-associated pathways and downregulated pathways critical for inner ear development, such as FGF and TGFb signaling.
Together these data reveal perturbation of developing RTMs that regulate normal cochlear development as a mechanism underlying CMV-mediated SNHL.
Oral tolerance inhibits DTH in the sensitization phase by Treg-mediated suppression of DC functions in skin dLNs
Authors: Akagi Arisa , Shibuya Rintaro , Hanakawa Sho , Kitoh Akihiko , Kabashima Kenji 
Published: November 2024

Abstract
Antigen (Ag)-specific skin immune responses such as delayed-type hypersensitivity (DTH) are suppressed by prior oral administration of Ag, depending on the induction of regulatory T cells (Tregs) in gut-draining lymph nodes (dLNs). Here, we aimed to clarify the exact phase and location where Tregs induced in gut-dLNs suppress DTH.
Prefeeding ovalbumin (OVA) attenuated DTH against OVA, consistent with previous studies. This attenuation was abrogated by in vivo depletion of Tregs. DTH responses elicited in OVA-fed and unfed mice, subsequent to the transfer of cells from dLNs of OVA-immunized skin, were comparable. In contrast, DTH responses were significantly attenuated in mice transferred with cells from dLNs of OVA-immunized skin in OVA-fed mice, suggesting that OVA-feeding inhibited the responses in the sensitization phase of DTH. Next, we assessed the capacity of DCs isolated from dLNs of OVA-immunized skin to prime OT-II T cells. OVA feeding did not affect T-cell priming capacity of DCs at 24 h post-immunization (d1), but impaired it at 48 h (d2). In vivo DC migration assay revealed OVA feeding did not affect the migration of Ag-bearing (Ag+) DCs to the dLNs. Expression levels of CD80 and CD86 on Ag+ DCs in tolerized mice were comparable to non-tolerized mice at d1 but lower at d2.
In conclusion, our data suggest that DTH responses in orally tolerized mice are inhibited in the sensitization phase via Treg-mediated suppression of DC functions in the skin-dLNs.
Expanded GATA3+ T regulatory cells fail to control germinal center responses during pulmonary fibrosis in humans and mice
Authors: Velez Tania , Yoon Young me , Hollinger Maile , Blaine Kelly , Lee Cathryn , Strek Mary , Guzy Robert , Sperling Anne 
Published: November 2024

Abstract
Interstitial lung disease (ILD) describes heterogenous conditions of progressive lung fibrosis. Interestingly, lung lymph nodes (LLN) of different types of ILD patients are enlarged and predicts survival outcomes. Our recent studies demonstrate that there are active germinal centers (GC) in the LLN of ILD patients, suggesting on-going antigen-specific responses. To determine whether these responses are dysregulated, we investigated T regulatory cells (Tregs). Our data shows that Tregs are expanded in the LLN of all ILD patients compared to controls. Intriguingly, there was a predominance of GATA3+ Tregs that co-expressed ICOS and CD137, indicating recent activation. GATA3+ Tregs can have detrimental effects in asthma models, but their role in pulmonary fibrosis is unknown. Thus, we hypothesize that GATA3+ Tregs in ILD patients may be failing to control GC responses and potentially facilitating lung fibrosis. To test this hypothesis, we utilized a mouse model of bleomycin (bleo)-induced pulmonary fibrosis. We find that GATA3+ Tregs expand in the lung and mediastinal LN (mdLN) of bleo-treated mice, and there is evidence of GC responses. Depletion of all Tregs is detrimental and leads to enlargement of mdLN. In contrast, specific depletion of GATA3 in Tregs is protective and does not lead to mdLN enlargement. In summary, these data show that GATA3+ Tregs may have roles in promoting pathogenic mechanisms during pulmonary fibrosis in humans and mice.
Neurophysiological phenotypes are uncoupled from toll-like receptor (TLR)-mediated systemic disease in a model of Systemic Lupus Erythematosus (SLE)
Authors: Stumpf Cecilia , Rodriguez Vanessa , Cuda Carla 
Published: November 2024

Abstract
SLE is a multisystemic autoimmune disease with diverse clinical presentations, including neuropsychiatric symptoms (NPSLE). Prior work implicates uncontrolled MyD88-dependent TLR activation, increased interferon regulatory factor 5 (IRF5) activity and elevated type I interferon (IFN) levels in disease. Immune complexes containing self-nucleic acids can activate endosomal TLRs 7/8/9, which require signaling adaptor MyD88 to modulate downstream gene expression through transcription factor 1) IRF7 to upregulate IFN, which can subsequently act on the IFN-α/β receptor (IFNAR) or 2) IRF5 to upregulate proinflammatory genes. SLE- and NPSLE-prone mice with conditional deletion of signaling mediators MyD88, IRF5 and IFNAR in dendritic cells and tissue resident-macrophages were generated. MyD88 and IRF5 deletion ameliorated systemic disease phenotypes including splenomegaly, lymphadenopathy and glomerulonephritis, but NPSLE-associated phenotypes in the brain, including expansion of total and disease-associated microglia, macrophages and extravascular T cells, persisted. In contrast, IFNAR deletion worsened systemic disease, yet reversed several NPSLE-associated phenotypes. These discoveries suggest an uncoupling of systemic and neurophysiological phenotypes in SLE. Namely, neurophysiological phenotypes manifest independently from the TLR-dependent pathway that drives systemic disease and are instead in part linked to aberrant signaling through IFNAR via mechanisms yet unexplored.
Characterizing inflammasome activation by bacterial amyloid curli complexes from biofilms in dendritic cells and its role in SLE
Authors: Mintri Shrutika , Grando Kaitlyn , Tükel Çagla , Fitzgerald Katherine A , Gallucci Stefania 
Published: November 2024

Abstract
Bacterial infections are a crucial environmental trigger for flares in Systemic lupus erythematosus (SLE). Although these infections are common in lupus patients, a precise mechanism of action remains unknown. Bacteria protect themselves from stresses by embedding in an extracellular matrix to form biofilms. Biofilms from bacterial species such as E. coli and Salmonella contain an amyloid protein called curli. Previous work from our labs has shown that curli/DNA complexes can accelerate lupus-like disease in mice, and increased levels of anti-curli antibodies are associated with flares in SLE patients, making these complexes important in autoimmunity. We had previously found that curli/DNA is a potent trigger of immune activation in dendritic cells (DCs) and macrophages. In macrophages, curli/DNA was also reported to induce IL-1b production through activation of the NLRP3 inflammasome. Here we expand these studies to delineate how curli/DNA complexes regulate IL-1b in murine and human DCs. Using curli/DNA alone or in combination with inflammasome stimuli, we found that curli/DNA stimulate pro-IL1b expression and inflammasome assembly, leading to caspase 1 activation, cleavage and release of mature IL-1B by DCs. However, we observed no cell death post inflammasome activation, suggesting a hyperactivated state in stimulated DCs. A deeper knowledge of this molecular mechanism might shed light on the role of inflammasome activation by bacterial infections in escalating SLE.
Deficiency in CD103DC function leading to decreased pTregs in female lupus-prone mice is due to defects in intestinal lamina propria stromal cell function that can be restored by male microbiota.
Authors: Ma Jing , Alard Pascale , Kosiewicz Michele 
Published: November 2024

Abstract
Active lupus in humans is associated with low Treg percentages, but not function. We have found that lupus-prone female BWF1 have decreased peripherally-derived Tregs (pTregs), but not function vs lupus-resistant male BWF1 mice. Gut CD103+ DC (CD103DC), the major pTreg inducer, function is decreased in female mice due to defects in the retinoic acid (RA) synthesis pathway, i.e., lower RALDH2 (critical enzyme) and higher Zfp36 expression (degrades RALDH2 RNA). Both normal CD103DC development/function and RALDH2 expression require exogenous RA. Treating female CD103DC with RA restored function and increased RALDH2 and decreased Zfp36 expression indicating CD103DC are not defective themselves. Lamina propria stromal cells (LPSC) are required for CD103DC development via RA and GM-CSF production. Female BWF1 LPSC had decreased RALDH2 expression/activity and GM-CSF suggesting lower CD103DC function is due to decreased LPSC function. We have found differences in female and male gut microbiota in BWF1 mice, and transfer of male microbiota to female mice protects against disease and increases survival, increases percentages/numbers of total Tregs/pTregs, and restores CD103DC and LPSC function that appears to be mediated by metabolites, phytol/phytanic acid, produced by male microbiota. Lower pTregs in female BWF1 mice may be due to defects in LPSC support of CD103DC development and can be restored by metabolites produced by male microbiota that contribute to protection from disease.
Exogenous IL-27 prevents the development of alopecia areata
Authors: Connell Samuel , Kahl Payton , Zhu Zhaowen , Lensing Maddison , Crotts Sydney , Bai Xue-Feng , Jabbari Ali 
Published: November 2024

Abstract
Alopecia areata (AA) is an autoimmune disease with a 2% lifetime incidence. Commonly presenting as defined patches of hair loss on the scalp, AA is characterized by the presence of T cells surrounding the hair bulb and is thought to result as a consequence of the breakdown of immune privilege of the hair follicle. IL-27 is a cytokine with context-dependent pro- and anti-inflammatory properties that has been used as a potential therapy in models of autoimmune diseases and cancer. The objective of this study was to determine if IL-27 has therapeutic potential in AA. To address this, we used an adeno-associated virus that drives the overexpression of IL-27 (AAV-IL27) in our skin-graft induction model of AA. We found that mice that received AAV-IL27 were fully protected from disease development and had minimal CD8 T cell infiltration into the hair follicles. Further, we saw an increase in IL-10 producing CD4 T cells, supporting a potential mechanism by which IL-27 prevents disease development. Interestingly, we found that mice treated with AAV-IL27 generated a robust population of NKG2D expressing CD8 T cells, which has previously been associated with the presence of disease. These results suggest that IL-27 may act in an immunoregulatory manner in AA, by promoting immunosuppressive T cells in the SDLNs. Further studies are needed to further define the specific mechanisms by which IL-27 contributes to the prevention of AA and its utility as a treatment for AA.
Skewing of UV-Induced Cell Death Pathways using TLR4 Ligands
Authors: Chaudhry Sumra , Williford Zachary , Downes Shae 
Published: November 2024

Abstract
Ultraviolet (UV) radiation induces DNA damage resulting in epidermal cell mutations and immunosuppression contributing to the formation of nonmelanoma skin cancer. UV-induced cellular damage is commonly associated with apoptosis characterized by a non-inflammatory cell death through the cleavage and activation of caspase-3 which requires Toll-like receptor 4 (TLR4) signaling to activate the apoptotic signaling cascade. TLR4 is a cell associated innate immune receptor and has been shown to contribute to UV-induced carcinogenesis. We hypothesize that skewing cell death from apoptosis to necroptosis using lipid A mimetics to reduce TLR4 expression through tolerization can reduce apoptosis and lead to inflammatory cell death. Hexa-acylated and tetra-acylated lipid A memetics from Yersinia pestis (Y. pestis) are used to tolerize TLR4 in thioglycolate-induced macrophages (ThioMΦ). This will likely lead to the ThioMΦ cells being less susceptible to UV-induced carcinogenesis. To analyze the role of TLR4 in UV-induced carcinogenesis, cells that are TLR4-proficient, TLR4-deficient, and TLR4 tolerized with lipid A were exposed to multiple doses of UVB radiation. UV-irradiated ThioMΦ cells were surveyed for markers of DNA repair and cell death mechanism. Our data indicates that exposure to lipid A attenuates TLR4-mediated apoptotic cell death and, likely, downstream immune suppression. TLR4 ligands may be useful in prophylactic treatment approaches against UV-induced carcinogenesis.
Complement receptor 2 as a novel therapeutic target to suppress germinal center-derived autoantibody production in a SLE mouse model
Authors: Rattan Ajitanuj , Zhu Danni Y , Holers V Michael , Huber Brigitte T , Carroll Michael C 
Published: November 2024

Abstract
Presence of spontaneous germinal center (GCs) in SLE patients correlates with the production of pathogenic, isotype-switched antibodies (Abs) and epitope spreading. In lupus mice, spontaneous GCs are a major site for self-reactive B cells to undergo clonal selection to self-antigens. Limited efficacy of current B cell-based lupus therapies highlights the need to explore alternative targets for inhibiting auto-Ab secreting B cells (ASCs) generation. We propose that complement receptor 2 (CD21) is a novel therapeutic target to block expansion of autoimmunity and pathogenic Ab production. To test this, we set-up mix bone marrow chimeras and adoptive transfer models with 564Igi lupus mice and human CD21-transgenic mice, which allowed us to selectively block CD21 function of either B cells or FDC, or both. CD21 blockade on B cells not only restricted recently activated B cells but also memory B cells (MBC) to participate in GC-derived ASC generation. CD21 blockade on FDCs intriguingly biased MBC fate towards ASC generation, though impeded recently activated B cell capacity to participate in GC response. Dual blockade of CD21 on B cells and FDC exhibited strongest inhibitory effect on GC-derived ASC generation and auto-Ab production. As expected, blockade of ASC generation by donor B cells further correlated with reduced Ab deposition and ameliorated kidney pathology. In brief, CD21 presents itself as a promising therapeutic target to suppress pathogenic auto-Ab generation in SLE.