bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel Association of Lyme disease, Age, and Atopic Dermatitis
Authors: Lee Brandon , Galloway Sarah , Strausz Satu , Shoham Maia , Hansen Paige , Mansfield Paul , Salomon Rachel , Torrez-Dulgeroff Laughing Bear , Saleem Atif , Gars Eric , Sanders Erin , Ollila Hanna , Weissman Irving L , Tal Michal Caspi 
Published: January 2023

Abstract
Borrelia burgdorferi is a bacterial spirochete that can cause Lyme disease (LD) after infecting a susceptible host. Immune responses to the bacteria are highly variable and host specific. The murine substrain, C3H/HeJ, is a frequently utilized model for LD. Interestingly, over a prolonged infection, mice develop dermatitis on tail skin, which shares critical features with human skin. Female C3H/HeJ mice aged 5–8 weeks, 1 year, or 2 years were infected intraperitoneally with 105 B. burgdorferi. Dermatitis was evaluated by gross examination and histology. Dermatitis worsened over the course of untreated infection, with ulceration, hemorrhaging, flaking, hair loss, and dark lesions as well as spongiosis and acanthosis. These features of dermatitis were present in infected mice after 1 year of age. This relationship among LD, atopic dermatitis, and host age seen in the C3H/HeJ mouse model is consistent with a large pool (342,499) of human epidemiological data from Finland. We identified 5,248 individuals with LD and 17,233 with atopic dermatitis in FinnGen. Retrospective analysis shows LD is associated with atopic dermatitis (OR = 1.91 [1.68 −2.37], P &lt; 2e−16). More visits due to LD complications (3 or more visits versus 1 visit) were associated with atopic dermatitis (OR = 2.19 [1.35–3.55], P = 0.0014) and risk of developing atopic dermatitis over time (HR = 2.26 [1.54–3.95], P = 0.0017). Data from mice and humans reveal a novel relationship among LD, age, and atopic dermatitis. Through defined pathological scoring, we demonstrate the onset of murine atopic dermatitis with B. burgdorferi infection, which is further exacerbated by host age at time of infection, and likewise report a similar association in human epidemiological data from FinnGen.
Research was supported by the Fairbairn Family foundation; Bay Area Lyme Foundation; the Younger family foundation; the Robert J. Kleberg, Jr., and Helen C. Kleberg Foundation; the Virginia and D. K. Ludwig Fund for Cancer Research; AML grant R01CA086017; the PCBC from NIHLB U01HL099999; as well as grant U19AI109662. M.C.T. was supported by Stanford Immunology training grant 5T32AI007290, and the NIH NRSA 1 F32 AI124558-01 award. L.B.T.D. was supported by a Stanford Diversifying Academia Recruiting Excellence fellowship. S.G. was supported by the California Institute for Regenerative Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Inflammatory responses to Listeria monocytogenes infection in the placenta
Authors: Seveau Stephanie 
Published: January 2023

Abstract
The immunological defense of the developing fetus is crucial for a successful pregnancy. The placenta plays key roles in protecting the fetus against rejection by the maternal immune system, while it ensures its defense against most pathogens. The mechanisms that orchestrate the placental immune functions are still poorly understood. The bacterial pathogen Listeria monocytogenes (Lm) breaches the maternal/fetal barrier, infects the placental chorionic villi, and reaches the fetus resulting in poor pregnancy outcomes. We studied the interplay between Lm and key players of the placental antimicrobial defense: trophoblasts (TCs), which are epithelial cells covering placental chorionic villi at the maternal/fetal interface, and placental macrophages (Hofbauer cells, or HBCs), which are the only leukocytes residing in chorionic villi. Both cell types form a critical immune barrier protecting the fetus from infection. We isolated human primary TCs and HBCs from healthy term placentas to study the Lm intracellular lifecycle as well as the cellular responses to infection (RNAseq and cytokine arrays). We found that both cell types were permissive to Lm infection and mounted a pro-inflammatory response to the pathogen including HBCs repolarization towards a pro-inflammatory phenotype favoring the innate immune responses. However, consistent with their placental homeostatic functions, TCs and repolarized HBCs maintained the expression of tolerogenic factors known to prevent maternal anti-fetal adaptive immunity. We will discuss our published studies (PMID 34399615 and 34367171) and recent data that teased apart the role of the Lm virulence factors in the inflammatory responses of placental cells.
Supported by NIH (R01AI157205, R21AI105588, R03AI149371)
Gasdermin D promotes hyperinflammation by triggering necroptosis in the presence of mitochondrial stress
Authors: Weindel Chi Gidley , Zhao Xiao , Martinez Eduardo , Bell Samantha L , Vail Krystal J , Coleman Aja K , VanPortfliet Jordyn J , Mabry Cory J , Li Pingwei , West A Phillip , Karpac Jason , Patrick Kristin L , Watson Robert O 
Published: January 2023

Abstract
Human genetic variants associated with mitochondrial dysfunction have been linked to chronic inflammatory diseases as well as susceptibility to infection. However, the mechanistic impact that these variants have on the immune system is poorly understood. We have discovered that macrophages harboring the common Parkinson’s disease associated variant, Lrrk2G2019S are more prone to cell death in response to both Mycobacterium tuberculosis (Mtb) infection and AIM2 inflammasome activation. Unexpectedly, the enhanced cell death in Lrrk2G2019S macrophages is driven by increased susceptibility to gasdermin D (GSDMD)-mediated mitochondrial pore formation, which releases accumulated mitochondrial ROS and pushes Lrrk2G2019S cells to undergo RIPK3-mediated necroptosis. Consistent with elevated necroptotic cell death, infection of Lrrk2G2019S mice with Mtb elicits dramatic hyperinflammation and exacerbated pathogenesis via enhanced neutrophil infiltration. Remarkably, expression of hLRRK2G2019S in Drosophila melanogaster recapitulates a similar phenotype, suggesting that Lrrk2G2019S plays an evolutionarily conserved role in regulating innate immunity. Our findings demonstrate that altered mitochondrial function can reprogram canonical innate immune and cell death pathways to elicit distinct immune outcomes, providing mechanistic insights into why mutations in LRRK2 are associated with susceptibility to chronic inflammatory and infectious diseases.
Supported by grants from the Parkinson’s Foundation (PF-FBS-1932), NIH (R01 AI125512), Michael J. Fox Foundation (grant 12185), and the Texas A&M Clinical Science and Translational Research (CSTR) Pilot Grant Program.
Aging augments type 2 cytokine responses in ILC2s leading to reparative, M2-like microglia
Authors: Mobley Alexis S , Hamlin Ashley , Garrido Jesus Bautista , Jung Joo Eun , McCullough Louise D , Aronowski Jaroslaw 
Published: January 2023

Abstract
Aging affects immunologic responses by a global suppression of the immune system, including dysregulation of cytokine mediators, leading to increased inflammation throughout all systems, termed inflammaging. However, understanding mechanisms of healthy aging can bypass this effect. Inflammaging also leads to poor outcomes during brain injury, making immune-targeting therapeutics tantamount to overall brain health and longevity. Two candidate immune cells microglia and group 2 innate lymphoid cells (ILC2s) may control immune responses in the aged brain Therefore, we hypothesized that ILC2s are the brains’ gatekeepers of microglia polarization to a reparative, M2-like phenotype under: (1) homeostatic conditions and (2) with aging. To address this, we used flow cytometry to quantify ILC2s between young and aged male and female C57Bl6/J mice, showing an age-related increase in aged males. Moreover, when we stimulated ILC2s, the data indicated an age-related increase in cytokine production in males. We also utilized conditioned media transfer experiments from stimulated young and aged ILC2s to quiescent microglia and assessed their morphologic, genomic, proteomic, and functional changes using microscopy, qRT-PCR, Western immunoblotting, and phagocytosis assays. We showed more complex microglia morphology (indicating microglial priming) and an increase in reparative mRNA, proteins, and phagocytic function in microglia, which was augmented by aged ILC2s. Taken together, we have defined the capacity of ILC2 soluble factors to polarize microglia to a reparative phenotype and maintain this in aging.
Supported by the NIH NINDS F31NS118983
Activation of TLR9 signaling in fibroblastic reticular cells enhances anti-tumor immunity in peritoneal tumor via suppressing peritoneal resident macrophage retention.
Authors: Deng Meihong 
Published: January 2023

Abstract
Immune checkpoint blockade (ICB) has been shown to improve the prognosis of patients with advanced malignancy; however, most patients do not respond to ICB therapy. Peritoneal resident macrophages (PRMs) are critical for peritoneal immunity in health and disease. A recent study has demonstrated that PRMs dampen the therapeutic efficacy of ICB via impairing anti-tumor CD8+ T cell immunity. Here we show that activation of TLR9, an endosomal DNA sensor, in fibroblastic reticular cells (FRCs) negatively regulates PRM retention. Mechanistically, TLR9 in FRCs suppresses retinol metabolism and thus suppresses GATA6 expression in PRMs. Notably, combined treatment of ODN1585, a TLR9 agonist, and anti-PD1 substantially improves the efficacy of anti-PD-1 immune checkpoint blockade therapies in MC-38 and CT26 colorectal carcinoma cell lines-induced peritoneal tumor in mice, evidenced by decreased tumor burden and mortality rate. The improvement is associated with an increase in the percent of CD8+ T cells and a decrease in the percent of CD39+ exhausted CD8+ T cells. Furthermore, global knockout of TLR9 or specific knockout of TLR9 in FRC diminished the beneficial effect of ODN1585 and anti-PD-1 combined treatment on tumor burden and survival. These data demonstrate the potential utility of the FRC-TLR9 signaling in modulating PRM retention to improve the therapeutic efficacy of ICB in peritoneal tumors.
Supported by grants from NIH / startup fund
A new mechanism of Treg cell dysfunction during HIV infection and propensity to oral cancer in people living with HIV
Authors: Pandiyan Pushpa 
Published: January 2023

Abstract
Mechanisms of immune-dysfunction associated with chronic viral infections remain nebulous. Residual systemic inflammation and mucosal immune dysfunction persist in people living with HIV despite anti-retroviral therapy, but the underlying immune processes are poorly understood. Here we show an altered immune landscape of the oral mucosa of HIV-positive patients on therapy involves increased TLR− and inflammasome signaling, localized CD4+ T cell hyperactivation, and counterintuitively, enrichment of regulatory T cells. HIV infection of oral tonsil cultures in vitro causes an increase in FOXP3+ cells expressing PD-1, IFN-γ, Amphiregulin and IL-10. These cells persist even in the presence of anti-retroviral drugs, and further expand when stimulated by TLR-2 ligands and IL-1β. Mechanistically, IL-1β upregulates PD-1 expression via AKT signaling and PD-1 stabilizes FOXP3 and Amphiregulin through a mechanism involving Asparaginyl Endopeptidase, resulting in FOXP3+ cells that are incapable of suppressing CD4+ T cells in vitro. Phenotypically similar cells are abundant in HIV-positive patients, and their presence strongly correlates with CD4+ T cell hyper-activation, suggesting diminished CD4+ T cell regulation in the oral mucosa in vivo. Taken together, this study provides unprecedented insights into the mechanism of FOXP3+ cell dysregulation and its potential role in mucosal dysfunction and cancer susceptibility in HIV patients.
Supported by NIH NIDCR R01 DE026923
Lipin-1 restrains lipid synthesis to promote proresolving macrophage function and disease resolution
Authors: Bamgbose Temitayo Taiwo , Schilke Robert M , Blackburn Cassidy M R , Woolard Matthew D 
Published: January 2023

Abstract
Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. Unresolved inflammation contributes to the pathophysiology of cardiometabolic diseases. The lipid metabolic state of macrophages influences their function. Lipid synthesis contributes to proinflammatory responses, while beta-oxidation is required for pro-resolving macrophage function. However, how lipid metabolism is regulated during macrophage activation is not well understood. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity that is proposed to act as a regulator of lipid metabolism. We have previously demonstrated that lipin-1 is atheroprotective and promotes wound healing. Within macrophages, lipin-1 is required for beta-oxidation and apoptotic cell engulfment, both key activities of pro-resolving macrophages. We investigated the contribution of lipin-1 in regulating lipid metabolism during pro-resolving macrophage responses using metabolomics, lipidomics, and Western blot analysis. IL-4 stimulation of macrophage promotes lipid catabolism; however, in lipin-1 KO bone marrow-derived macrophages, we observed the production of metabolites that contribute to lipid synthesis, decrease phosphorylation of ACC (a marker of lipid synthesis) and a build-up of free fatty acids. We also observed increased ceramides in lipin-1 KO macrophages and a decrease in pras40 phosphorylation, which is consistent with increased ceramide synthesis. These results suggest that lipin-1 restrains de novo lipid synthesis and ceramide production to promote beta-oxidation for optimal pro-resolving macrophage function.
Supported by1-R01HL131844-04 grant from NHLBI/NIH
DNA-PKcs is required for the activation and cytotoxicity of CD8+ effector T cells
Authors: Burdine Marie , Azevedo-Pouly Ana , Appell Lauren , Barker Melanie , Waldrip Zachary , Burdine Lyle 
Published: January 2023

Abstract
Antigen-mediated activation of naïve CD8+ T cells and their differentiation into cytotoxic cells is regulated by a series of signaling mechanisms designed to maintain T cell homeostasis and proper immune responses. Given that cytotoxic CD8+ T cells are critical to the elimination of cancerous or virally infected cells as well as mediators of autoimmune diseases, GVHD and allogenic organ rejection, it is critical that we continue to dissect these mechanisms to identify promising targets for T cell modulation in the clinic. Previously, we have shown that inhibition of the kinase DNA-dependent protein kinase catalytic subunit (DNA-PKcs) reduces activity of the transcription factors NFAT, NFκB and EGR1 and production of cytokines including IL2, IL6 and IFNγ in TCR-activated T cells. Using pharmacological inhibitor and genetic approaches, we provide evidence for a novel role of DNA-PKcs in CD8+ T cell activation. Inhibition of DNA-PKcs abrogated anti-CD3/CD28 activation of CD8+ T cells as evident by reduced expression of the activation markers CD69 and CD25. Additionally, loss of DNA-PKcs activity inhibited aerobic glycolysis and proliferation of OTI-CD8+ T cells following SIINFEKL peptide stimulation. This caused reduced OTI-CD8+ T cell killing of MC38.OVA tumor cells and expression of IFNγ and the cytotoxic genes perforin and granzyme B. These results were recapitulated in DNA-PKcs-deficient CD8+ T cells isolated from an inducible Cre/DNA-PKcsfl/fl mouse model where loss of DNA-PKcs reduced expression of CD69 and CD25, IFNγ production and altered cellular metabolism. The identification of a function for DNA-PKcs in CD8+ T cell activation highlights the therapeutic potential of DNA-PKcs inhibitors on immune-related diseases.
Supported by Center for Pediatric Translational Research NIH COBRE P20GM121293
Inhibition of distinct glycolytic enzymes produces differential effects on CD4 T cell function
Authors: Godfrey Wesley H , Kornberg Michael 
Published: January 2023

Abstract

Background
When T cells are activated, they upregulate glycolysis and take on a requisite Warburg phenotype. In this study, we evaluated the effect of inhibiting two distinct glycolytic enzymes, GAPDH and PGAM, on CD4 T cell differentiation and effector activities in order to gain a mechanistic understanding of the relationship between glycolysis and T cell function.

Methods
To evaluate the effect of GAPDH inhibition on T cell function, we cultured naïve murine CD4+ T cells under Th1 or Treg polarizing conditions and treated with either the GAPDH inhibitor heptelidic acid or the PGAM inhibitor EGCG. We then assessed either IFNγ production or identified CD25+Foxp3+ cells in response to either Th1 or Treg polarization, respectively. To evaluate the impact of GAPDH inhibition in vivo, we used the MOG35–55 experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis (MS) and compared neurological function in mice treated with vehicle or heptelidic acid.

Results
We found that GAPDH inhibition had a potent anti-inflammatory effect on T cells in vitro, drastically reducing IFNγ production at both the transcriptional and protein levels. Interestingly, PGAM inhibition had the opposite effect, potently blocking Treg differentiation. In the EAE mouse model of MS, heptelidic acid attenuated the disease course, indicating that GAPDH inhibition is anti-inflammatory in vivo.

Discussion
GAPDH inhibition was anti-inflammatory in vitro and in vivo, while PGAM inhibition had the opposite effect. These findings suggest that the functional consequences of glycolysis inhibition depend on the specific enzymes targeted, which has both mechanistic and therapeutic implications for the role of glycolysis in immune cell function.
Intestinal and tracheal microbiomes inhibit in vitro growth of Coccidioides immitis
Authors: Tejeda-Garibay Susana , Diep Anh , Hoyer Katrina K 
Published: January 2023

Abstract
Valley fever is a disease caused by Coccidioides, a fungal pathogen, and is frequently misdiagnosed as community acquired bacterial pneumonia and treated with several rounds of antibiotics prior to accurate diagnosis. Antibiotic treatment changes the microbiome repertoire and host immunity; the impact of these microenvironmental changes on Coccidioides invasiveness is unknown. A soil microbial antagonist related to Bacillus subtilis inhibits in vitro growth of Coccidioides immitis through a clear zone of inhibition between fungi and bacteria. Whether host microbiota also could inhibit Coccidioides is unknown. To assess host microbiota inhibition capabilities against Coccidioides, we performed two types of inhibition assays. A 50/50 inhibition assay was performed in which the host microbiota and Coccidioides were placed in direct competition simultaneously on agar plates. A spike in inhibition assay was also performed in which the host microbiota was allowed to reach ~80% confluency, to mimic an established in vivo microbiome, before spiking in Coccidioides. The area of growth was observed and measured at day 4, 7, and 11. Our in vitro data indicate that specific intestinal and tracheal host microbiome species inhibit Coccidioides growth. To assess if partial in vitro depletion of host microbiota allows greater Coccidioides growth, antibiotic disc diffusion assays were performed. Our data suggests that depleting commensal microbiomes, allows a niche for Coccidioides growth. These in vitro findings could have clinical relevance and shape the way physicians assess prescription of antibiotics and coccidioidomycosis diagnosis. Experiments to identify the inhibitory microbiota and proteomic interactions are ongoing.
Arresting microbiome development limits immune system maturation and resistance to infection
Authors: Silverman Michael A , Lubin Jean-Bernard , Denu Lidiya , Green Jamal , Duranova Tereza , Lanza Mathew , Wynosky-Dolfi Meghan , Brodsky Igor E , Planet Paul 
Published: January 2023

Abstract
The transition from milk to solid food is a critical period in post-natal human development. Weaning coincides with a dramatic and rapid maturation of both the microbiome and immune system. Whether these weaning induced changes in commensal communities shape immune system development and susceptibility to enteric infection remains unknown. Here we find maturation of the microbiome during weaning is required for proper immune system development and protection against enteric infection. To this end, we developed a stable gnotobiotic mouse model of the early-life microbiome composed of a representative nine-member consortium of phylogenetically diverse microbes found pre-weaning, designated as Pediatric Community (PedsCom). PedsCom efficiently colonized germfree adult mice and was vertically transmitted to offspring. Unexpectedly, the composition of PedsCom was unaffected by the transition from a milk-based to a fiber rich solid food diet. This permitted us to study adult mice with a pre-weaning intestinal microbiome. We find that arresting intestinal microbiome maturation in PedsCom mice limited immune system development. PedsCom mice displayed decreased both peripheral regulatory T cells accumulation and Immunoglobulin A production, hallmarks of microbiota-driven immune development. Consistent with defects in maturation, adult PedsCom mice retain high susceptibility to Salmonella infection characteristic of young mice and humans. Altogether, our work illustrates how the post-weaning transition in intestinal microbiome composition is essential for normal immune maturation, and protection from enteric infection.
Supported by 1R21AI146629-01A1
CSF-1 maintains pathogenic but not homeostatic myeloid cells in the central nervous system during autoimmune neuroinflammation.
Authors: Hwang Daniel , Seyedsadr Maryam S , Ishikawa Larissa Lumi Watanabe , Boehm Alexandra , Sahin Ziver , Casella Giacomo , Jang Soohwa , Gonzalez Michael V , Garifallo James P , Hakonarson Hakon , Zhang Weifeng , Xiao Dan , Rostami Abdolmohamad , Zhang Guang-Xian , Ciric Bogoljub 
Published: January 2023

Abstract
The receptor for colony stimulating factor 1 (CSF-1R) is important for the survival and function of myeloid cells that mediate pathology during experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). CSF-1 and IL-34, the ligands of CSF-1R, have similar bio-activities but distinct tissue and context-dependent expression patterns, suggesting that they have different roles. This could be the case in EAE, given that CSF-1 expression is upregulated in the CNS, while IL-34 remains constitutively expressed. We found that targeting CSF-1 with neutralizing antibody halted ongoing EAE, with efficacy superior to CSF-1R inhibitor BLZ945, whereas IL-34 neutralization had no effect, suggesting that pathogenic myeloid cells were maintained by CSF-1. Both anti-CSF-1 and BLZ945 treatment greatly reduced the number of monocyte-derived cells and microglia in the CNS. However, anti-CSF-1 selectively depleted inflammatory microglia and monocytes in inflamed CNS areas, whereas BLZ945 depleted virtually all myeloid cells, including quiescent microglia, throughout the CNS. Anti-CSF-1 treatment reduced the size of demyelinated lesions and microglial activation in the grey matter. Lastly, we found that bone marrow-derived immune cells were the major mediators of CSF-1R-dependent pathology, while microglia played a lesser role. Our findings suggest that targeting CSF-1 could be effective in ameliorating MS pathology, while preserving the homeostatic functions of myeloid cells, thereby minimizing risks associated with ablation of CSF-1R-dependent cells.
National Multiple Sclerosis Society (RG-1803-30491) National Institutes of Health T32 training grant (T32AI134646, NIAID)