bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sensory neurons shape allergic Type 2 inflammation in the sinonasal tract
Authors: Ortiz-Carpena Jorge F , Pastore Christopher , Hung Li-Yin , Kohanski Michael A , Vaughan Andrew E , Cohen Noam A , Herbert De’Broski R 
Published: January 2023

Abstract
Whether neuro-immune interactions regulate homeostasis vs. inflammation within the sinonasal tract is entirely unknown. Transient receptor potential vanilloid 1 ion channel (TRPV1+)-expressing sensory neurons of the trigeminal ganglion (TG) innervate the upper airway near sinonasal tuft cells (STC), a rare lineage of epithelial cells that initiate inflammation in the intestine by secreting pro-Type 2 cytokines. Given the vicinity of STC and TG neurons, we hypothesized that STC function(s) may be at least partially controlled by neuronal inputs. A mouse model of sinonasal allergic inflammation was developed using intranasal administration of a fungal allergen mix (FAM) that mimics key aspects of chronic rhinosinusitis pathophysiology, including increased numbers of sneezing bouts, STC, eosinophils, and levels of interleukin (IL)-25 in the sinonasal fluid. Our data show that FAM also evokes the release of neuropeptides substance P and neuromedin U from TG neurons. Also, chemical ablation of TRPV1+ neurons significantly reduces STC expansion and eosinophil accumulation, which collectively suggests that TRPV1+ sensory neurons produce factors that promote STC to release Type 2 cytokines driving allergic disease pathophysiology. Ongoing studies are designed to uncover important insight(s) into how STC/sensory neuron interactions are involved in the pathogenesis of allergic diseases in the sinonasal tract.
Supported by grants from NIH (U01 AI163062, R01 AI164715, and R01 AI123173) awarded to DRH.
Inhibiting glycolysis by targeting the enzyme PFKFB3 restricts macrophage anti-mycobacterial activity and neutrophil phagocytosis of Mycobacterium tuberculosis.
Authors: Lane Daniel Scot , Talukdar Priyanka , Junecko Beth Fallert , Mattila Joshua T 
Published: January 2023

Abstract
Mycobacterium tuberculosis (Mtb) causes tuberculosis (TB), a leading cause of infectious disease-related mortality around the world. Myeloid cells are important in TB as Mtb host cells and anti-Mtb effector cells but the factors that differentiate these roles are not clearly defined. Immunometabolism is a driver of immune function and may be an important determinant of this interaction and represents a potential target for host-directed therapies against TB. To better understand how immunometabolism relates to TB, we incubated macrophages and neutrophils from Mtb-infected macaques with a panel of metabolic inhibitors and measured how this affected cellular responses to Mtb infection. Specifically, we targeted glycolysis, oxidative phosphorylation, and fatty acid oxidation and measured how this affected macrophage and neutrophil phagocytosis, macrophage control over Mtb viability and replication, and neutrophil production of extracellular traps. We found that targeting glycolysis by inhibiting PFKFB3, a rate-limiting enzyme in glycolysis, reduced macrophage anti-Mtb activity and neutrophil phagocytosis, while inhibition with the glucose analog 2-DG did not. In contrast, incubating cell-free mycobacteria with PFKFB3 inhibitors severely inhibited their growth, suggesting that these bacteria use different metabolic pathways in cells and culture to survive. Inhibiting oxidative phosphorylation with metformin or fatty acid oxidation with etomoxir did not change how macrophages or neutrophils responded to Mtb or affect mycobacterial growth in culture. These results indicate a role for immunometabolism in myeloid responses to Mtb and may inform efforts for development of metabolism-targeted therapies for TB.
Supported by grants from NIH (R01AI134183)
CD200 is required to control LPS-induced lung inflammation.
Authors: Patoine Dany , Bouchard Karine , Bissonnette Elyse , Lauzon-Joset Jean-Francois 
Published: January 2023

Abstract

INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a severe lung inflammatory disease caused by a variety of precipitants, including SARS-CoV-2 (COVID-19). In addition to excessive inflammation, ARDS is characterised by the dysregulation of anti-inflammatory pathways, including CD200/CD200R pathway.

OBJECTIVE
To investigate the role of CD200/CD200R pathway in lung ARDS inflammatory response.

METHODS
LPS was administered intratracheally to induce ARDS in Sprague-Dawley CD200 KO and wild type (WT) rats. Inflammation was evaluated using bronchoalveolar lavage (BAL) cellularity. Lung injury was measured by total protein level in BAL fluid, and levels of proinflammatory cytokines (TNF, IL-6) and chemokines (CXCL2, CCL2) were determined in BAL supernatants. In a second experiment, recombinant CD200Fc was administered to KO rats to restore the anti-inflammatory response.

RESULTS
Although there was no difference in total BAL cell counts at 3 h, cell recruitment was greater in CD200 KO rats given the low cell number in naïve KO rats. BAL of KO rats had higher levels of TNF, IL-6, CXCL2, and CCL2 compared to WT rats. Total protein level in BAL was higher in CD200 KO rats, implying more pronounced pulmonary edema. CD200Fc administration in KO rats significantly decreased levels of TNF and CCL2 in BAL, suggesting an attenuation of the inflammatory response.

CONCLUSION
This study shows that ARDS inflammatory response is exacerbated in absence of CD200 in an experimental model of ARDS in rats and that CD200 supplementation alleviates this phenotype. Further analyses will be needed to better understand the contribution of different cell types expressing CD200 to control lung inflammatory response resulting from ARDS.
Supported by grant by CIHR and IUCPQ fondation.
Modulating levels of cell surface CD6 is a novel mechanism for regulating T cell activity.
Authors: Chu Dalena Ngoc , Tiet Phoi , Marrocco Valeria , Ampudia Jeanette , Connelly Stephen , Ng Cherie 
Published: January 2023

Abstract
CD6 is a co-stimulatory receptor expressed on the surface of T cells that promotes immune synapse formation, T cell activation, and migration into tissues by engaging its ligand, ALCAM. CD6high cells have been described to be more pathogenic relative to CD6low cells. Furthermore, T cells in CD6 knockout mice have decreased proliferation and inflammatory responses. Hence, a therapeutic that can modulate surface levels of CD6 may have favorable outcomes for autoimmune/inflammatory conditions. We recently demonstrated that the anti-CD6 mAb, itolizumab, induces proteolytic cleavage of cell surface CD6. The goal of the work shown here is to characterize the mechanism of cleavage and the downstream functional consequences of reduced cell surface CD6. Treatment of PBMCs with itolizumab induces CD6 cleavage from the cell surface and a concomitant increase in the soluble form detected in the supernatant. Itolizumab-induced loss of CD6 was not observed with isolated T cells, however CD6 levels were reduced by 87% when T cells and monocytes were cocultured with itolizumab. The cleavage of CD6 is initiated through rapid cell-to-cell contact between T cells and monocytes via FcγRI. The dose-dependent reduction in surface levels of CD6 positively correlates with decreases in T cell activation markers such as CD25, PD-1, and CD71 (Pearson, p&lt;0.001) and cytokine production including IL-2 (p&lt;0.01) and TNFα (p&lt;0.05). Itolizumab-treated cells are also less alloreactive as shown by a reduction in proliferation and cytokine production of responder cells in a mixed-lymphocyte reaction. This data further supports targeting CD6 as an effective means to inhibit pathogenic T cell activity in the treatment of autoimmune and inflammatory diseases.
BATF controls T cell differentiation during chronic antigen stimulation
Authors: Titcombe Philip J , Morales Milagros Silva , Zhang Na , Mueller Daniel L 
Published: January 2023

Abstract
CD4+ T cells preserve self-tolerance in the periphery by exerting active suppression as regulatory T cells (Treg) or entering an inactive state known as anergy. Recent evidence suggests that anergy occurs naturally within a subpopulation of polyclonal CD4+ T cells and can generate precursors to Foxp3-expressing Treg cells. To identify transcription factors (TFs) underlying T cell anergy induction and its potential plasticity, we sorted polyclonal CD4+ T cell subsets from mice for downstream sequencing-based interrogation. Anergic CD44high Foxp3− CD73high FR4high Nrp1+ T cells were compared to effector-memory, Treg, and naïve T cell populations. Integrated ATAC-seq and RNA-seq analysis revealed a distinct program in the anergic T cell subpopulation. The anergy signature was driven by bZIP/AP-1 subfamily (Batf, Maf) and NFAT family (Nfatc1) transcription factors. Anergy-enriched TFs were then investigated in antigen-specific T cell tolerization systems where Batf knockdown led to altered expansion and minimal Treg cell differentiation. BATF was furthermore required for anergy-derived Foxp3+ Treg cell generation. Our data indicate that BATF orchestrates the transition to chronically-stimulated T cell differentiation states.
Supported by grants from the NIH (T32 AI007313, P01 AI035296) and RRF (Future Physician Scientist Award)
Comprehensive comparison of adaptive immune responses to inactivated SARS-CoV-2 vaccine between young and old
Authors: Xiao Chanchan , Ren Zhiyao , Zhang Bei , Mao Lipeng , Wang Pengcheng , Liang Xiaofeng , Luo Oscar Junhong , Chen Guobing 
Published: January 2023

Abstract
Aging is a critical risk factor for SARS-CoV-2 vaccine efficacy. Although low humoral immunity in the elderly was observed in mRNA and recombinant protein vaccination, it is still unclear how inactivated SARS-CoV-2 vaccine stimulates humoral and cellular immunity in elderly in the real world. Here, combining neutralizing antibody, tetramer stained CD8 T cells, transcriptome, and single cell TCR-seq examinations, we comprehensively compared immune responses before and after inactivated SARS-CoV-2 vaccination between 121 young and 48 old donors. Our data demonstrated that the inactivated SARS-CoV-2 vaccine can successfully induce antibody and T cells responses in the old people, although the responses were slower and weaker than young adults. The mechanism of impaired immune responses in elderly is likely due to altered immune cell function and decreased BCR and TCR repertoire diversity. In addition, impaired immune response due to mutant epitopes from SARS-CoV-2 variants raises concerns for future vaccine design.
This work was supported by grants from the National Key Research and Development Program of China (2018YFC2002003 to G.C., 2021YFC2009400 to G.Z.), the Natural Science Foundation of China (U1801285 to G.C., 81971301 and 32050410285 to O.J.L.)
BCAP plays a central role in regulating canonical M2 macrophage polarization upon various cell extrinsic signals
Authors: Kawarizadeh Kiana , Warrick Kathy , Pasare Chandrashekhar 
Published: January 2023

Abstract
Macrophages acquire either pro-inflammatory or anti-inflammatory states following cell extrinsic stimuli. Upon microbial recognition, macrophages differentiate into a pro-inflammatory state referred to as M1 phenotype. Subsequently, clearance of the insult facilitates the transition of M1 macrophages into an anti-inflammatory M2 phenotype to repair damaged tissue and maintain homeostasis. Recent work has identified B-cell adaptor for PI3K (BCAP), acting downstream of TLRs, as a key player in facilitating this transition to switch macrophages from expression of pro-inflammatory genes to repair genes. Whether BCAP also plays a role in macrophage differentiation upon sensing other extrinsic signals remains currently unknown. For example, the anti-inflammatory cytokine Interlekin-4 (IL-4) can drive macrophage differentiation into a M2 phenotype. We found that, following IL-4 stimulation, BCAP deficient macrophages exhibited a defective M2 gene program as revealed by reduced expression of Arg1, Klf4, and Retnla. Furthermore, we found that IL-33 mediated M2 macrophage generation was also hampered in the absence of BCAP. These findings reveal that in addition to acting as a regulator of M1 to M2 transition, BCAP is a critical node for detecting cell extrinsic signals that drive canonical M2 polarization. The mechanisms by which BCAP regulates IL-4R and IL-33R mediated M2 gene program as well as the impact of BCAP on the phenotype of tissue resident macrophages is currently being investigated.
Supported by grants from NIH (R01 AI113125)
Lipin-1 integrates lipid metabolism with macrophage function to promote inflammation resolution
Authors: Woolard Matthew D , Blackburn Cassidy , Schilke Robert , Bamgbose Temitayo 
Published: January 2023

Abstract
Free fatty acid accumulation in macrophages alters cellular metabolism, leading to failed inflammation resolution that contributes to cardiometabolic pathologies such as atherosclerotic cardiovascular disease. Free fatty acids are either broken down by β-oxidation, stored in glycerolipids, or incorporated into sphingolipids (e.g., ceramides). Ceramide synthesis inhibits several pro-resolving macrophage functions, such as β-oxidation and efferocytosis, needed for inflammation resolution. The regulatory signals that control free fatty acid incorporation into lipids (e.g., lipid channeling) for proper macrophage function are not well understood. Lipin-1 is a phosphatidic acid phosphatase with an independent transcriptional coregulatory activity that controls cellular lipid homeostasis. Using genetically engineered mice and bone marrow-derived macrophages, we investigated the contribution of lipin-1 on macrophage pro-resolving functions. Mice lacking myeloid-specific lipin-1 had defects in the clearance of apoptotic cells in a zymosan model of inflammation resolution, and these mice had increased atherosclerotic plaques and necrotic cores in a model of atherosclerosis and a delay excisional wound closure. Bone marrow-derived macrophages lacking lipin-1 showed a striking pattern of dysregulated lipid metabolism in which il-4 stimulation promoted ceramide synthesis over β-oxidation. Additionally, lipin-1 deficient macrophages had reduced phagocytosis of apoptotic cells. Our work provides evidence that lipin-1 promotes β-oxidation while inhibiting ceramide synthesis during free fatty acid accumulation in macrophages to allow for responses that promote inflammation resolution.
Supported by grants from NIH (1 R01HL131844-04) and NIH (1P20GM134974-01A1)
Modulation of myeloid cell functions by long noncoding RNAs RN7SK and HCG11
Authors: Naqvi Raza Ali , Ahmad Imran , Estepa Araceli Maria Valverde , Naqvi Afsar 
Published: January 2023

Abstract

Objective
Expressional dynamics of long noncoding RNAs (lncRNA)” regulates a gamut of biological processes including immunity. Role of lncRNA in response to oral pathogens and their regulatory impact on the innate immune functions of myeloid cells remain poorly explored. Therefore, we hypothesize that periodontal pathogens may cause the alteration of lncRNA profiles in myeloid cells and modulate their innate immune functions.

Method
CD14+ monocytes sorted from human PBMCs were differentiated into macrophages (MΦ) or dendritic cells (DC), and challenged with periopathic bacteria (A. actinomycetemcomitans [Aa] and P. gingivalis [Pg] for 4, 12 or 24 h. lncRNA expression was done at these time points by RT-qPCR array. Differentially expressed lncRNAs were assessed for: 1) cell migration, 2) phagocytosis, and 3) antigen uptake/processing in . Cell surface markers were analysed by flow-cytometry.

Result
Challenge of DCs with Pg, Pg LPS, Aa, and Aa LPS separately result in the differential expression of 21 lncRNAs (19 up, 2 down). Knockdown of LncRNA, SNHG11, NUTM2A-AS1, MCM3AP-AS1, JPX, and HCG11 (upregulated) and RN7SK (downregulated) were used to evaluate myleoid cell functions. HCG11 knockdown revealed attenuation of cell migration, while RN7SK significantly enhanced antigen uptake/processing in APCs . Importantly, RN7SK knockdown results in downregulation of M2 Mϕ surface markers (CD163, CD206 or Dectin) and concomitant increase in M1 Mϕ markers (MHC II or CD32) suggesting its critical role in macrophage polarization.

Conclusion
Our results show that periodontal pathogens alter lncRNA profiles and impair innate immune functions in myeloid cells, thereby suggesting critical roles of lncRNAs in periodontopathogenesis.
Supported by NIH/NIDCR R03 DE027147, R01DE027980, and R21DE026259 to AN.
Role of Grail in intestinal inflammation
Authors: Nurieva Roza I , Zhao Yang-Zhi , Alekseev Andrei , Galkina Elena , Kim Sang T 
Published: January 2023

Abstract
Intestinal homeostasis depends on interaction between the microbiota and host immune system, and disruption of this balance results in predominance of inflammatory responses leading to inflammatory bowel disease. However, to date, precise cell-intrinsic regulatory mechanisms that controls intestinal inflammation are poorly understood. Here we show that expression of the E3 ubiquitin ligase Grail is diminished in colon tissues of mice with colitis and Grail deficiency leads to increased susceptibility to colitis. Importantly, Grail deficiency disrupted pro-/anti-inflammatory balance towards inflammatory immune responses at the steady state and during colitis. Mechanistically, loss of Grail intrinsically diminished the expression of IL-10 and IL-10 receptor (IL-10R) by adaptive and innate immune cells in colonic mucosa. Besides the intestinal immunity, Grail deficiency leads to a decrease in microbial diversity and an enrichment of pro-inflammatory microbiota. Thus, Grail plays a protective role during intestinal inflammation by supporting regulatory immune responses and shaping the microbiota.
Epigenetic Modulation of Class-switch DNA Recombination to IgA by miR- 146a through Downregulation of Smad2, Smad3 and Smad4
Authors: Li Shili , Morales Grecia , Daw Cassidy C , Chupp Daniel Phillip , Fisher Amanda Dee , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
IgA is the predominant isotype at intestinal mucosae, where it plays a critical role in homeostasis and first line of immune protection. Class-switch DNA recombination (CSR) to IgA is directed by TGF-b which induces activation of Smad2 and Smad3 transcription factors. Activated Smad2/Smad3 dimers are recruited with Smad4 to IgH α locus Iα promoter to activate germline Iα-Cα transcription, the first step in CSR to IgA. Epigenetic factors, such as microRNAs, regulate immune cells and, as we have shown, modulate the antibody response in a B cell- intrinsic fashion. We found that miR-146a targets Smad2, Smad3 and Smad4 mRNA 3’UTRs, and keeps CSR to IgA in check in resting B cells. Enforced miR-146a expression in B cells aborted CSR to IgA by decreasing Smad levels. Induction of CSR to IgA, as directed by TGF-b, downregulated B cell miR-146a, thereby reversing the silencing of Smad2, Smad3 and Smad4, which, once expressed, led to recruitment of Smad2, Smad3 and Smad4 to Iα promoter for activation of germline Iα-Cα transcription. miR- 146a−/− mice significantly increased circulating levels of total IgA, but not IgM, IgG or IgE, and heightened the specific IgA antibody response to OVA. In miR-146a−/− mice, this was associated with increased IgA+ B cells in intestinal mucosae, increased amounts of fecal free and bacteria-bound IgA, kidney IgA deposition and IgA nephropathy. The B cell-intrinsic role of miR-146a in repression of Smad2, Smad3 and Smad4 and CSR to IgA was confirmed in miR-146a −/− B cells in vitro and in vivo in mixed bone marrow μMT/miR-146a−/− chimeric mice. Thus, by specific inhibition of Smad2, Smad3 and Smad4 expression, miR-146a plays an important and B cell intrinsic role in modulation of CSR to IgA and the IgA antibody response.
Supported by NIH grants AI 079705, AI 105813, AAI 167416 and LRA grant 641363 to PC.
Proteasome inhibition induces p53 driven apoptosis in early activated B-cells
Authors: Ochoa Trini , Allman David 
Published: January 2023

Abstract
Proteasome inhibition is a useful therapeutic strategy against plasma cell disorders in autoimmunity, neoplasias, and transplant rejection. However, how bortezomib induces cell death and the transcription factors that are involved in its execution are not well characterized. In this study, we aim to address the mechanism of action of proteasome inhibitors in plasma cells and in early precursor activated B-cells. We immunized mice with the hapten-protein conjugate nitrophenyl chicken-gamma-globulin (NP-CGG) and validated depletion of plasma cells and germinal center B-cells in vivo. At steady-state, we utilized B220 expression as a surface marker for newly-formed plasma cells and determined that bortezomib primarily depletes newly-formed plasma cells. To gain more mechanistic insight on how bortezomib affects newly-formed plasma cells, we employed an in vitro culture system of murine-derived primary follicular B-cells that were stimulated with CPG, IL-4, and IL5, to promote differentiation into the plasma cell fate. We find that deletion of the ER-stress induced transcription factor CHOP rescued in vitro generated plasma cells from low-dose bortezomib treatment. In addition, we identify the transcription factor p53 as a key inducer of apoptosis in in vitro generated early activated B-cells. Deletion of p53 rescued cells from apoptosis and reduced the number of cells expressing cleaved caspase-3 in response to bortezomib treatment. In conclusion, we have identified two transcription factors that are involved in bortezomib-induced cell death in B-lineage cells.
Supported by NIAID Diversity Supplement: R01AI139123
Flagella and indole produced by commensal bacteria protect the intestinal barrier to prevent food allergy
Authors: Kemter Andrea Maria , Patry Robert T , Arnold Jack , Campbell Evelyn , Hesser Lauren A , Ionescu Edward , Nagler Cathryn 
Published: January 2023

Abstract
Lifestyle-induced changes to the diversity of the commensal microbiota have been causally linked to the increasing prevalence of food allergies and other non-communicable chronic diseases. We have shown that bacteria from the Clostridia class prevent an allergic response to food by eliciting an IL-22 dependent barrier protective response that limits allergen access to the systemic circulation. We have now examined the mechanisms by which commensal Clostridia induce this allergy-protective effect. We identified taxa in a consortium of Clostridia that possess flagella and produce indole, which are ligands for TLR5 and AhR, respectively. Lysates and flagella isolated from this consortium induced IL-22 in mouse intestinal explants. IL-22 was not induced in explants from mice in which TLR5 or MyD88 was knocked out globally or conditionally in CD11c+ cells. Treatment with the commensal flagellar isolate also reduced detection of intragastrically administered FITC dextran in the serum of antibiotic-treated mice. Similarly, indole exposure induced IL-22 in intestinal explants and reduced intestinal permeability to FITC dextran. Importantly, AhR signaling in RORγt+ cells was necessary for IL-22 induction by flagella. These results suggest that flagella and indole act synergistically to prevent an allergic response. Finally, we have isolated and characterized two Clostridial taxa which bear flagella and produce indole. We hypothesize that germ-free mice colonized with these two taxa will exhibit improved IL-22 dependent barrier function and be protected against an allergic response. Our work reveals novel features of Clostridia key to their allergy-protective capability which may be further exploited to develop therapeutics.
Supported by NIH AI106302 and the Bunning Professorship Endowment Fund