bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disturbances in Chemokine Pathways as a Mechanism for Poor Immune Containment of MTB in the setting of HIV Co-infection
Authors: Martinez-Martinez Yazmin Berenice , Huante Matthew B. , Chauhan Sadhana , Golovko George , Fofanov Yuriy , Gelman Benjamin , Endsley Janice 
Published: January 2023

Abstract
Tuberculosis (TB) is one of the ten top causes of death worldwide and the leading cause in people living with Human Immunodeficiency Virus (HIV). The loss of function by diverse leukocyte populations and poor organization of the protective granuloma structure due to HIV infection is associated with poor immunity and increased proliferation of Mtb bacilli in co-infection. We employed our humanized mouse model of Mtb and HIV co-infection to investigate the HIV-mediated disturbances in the chemokines and chemokine receptors that regulate the recruitment, activation, and localization of inflammatory leukocytes at sites of pulmonary infection. Lung tissue of mice that were non-infected or infected with Mtb, HIV, or Mtb/HIV was used for multiplex ELISA of chemokine profiles in supernatants and for high throughput RNA sequencing to identify differential transcription of chemokine and chemokine receptor genes. Our results show that Mtb infection of humanized mouse lung activates human chemokine pathways important for recruitment and effector function of leukocytes at sites of infection such as CXCL1, CXCL5, and CCL2. Co-infection with HIV, however, activated differential transcription of several chemokines and chemokine receptor families, compared to Mtb mono-infection. These outcomes were associated with greater bacterial and viral burden in co-infected animals and may identify candidate mechanisms for host directed therapies to reduce aggressive TB in those living with HIV.
Early B cell protein λ5 affects skeletal homeostasis
Authors: Khass Mohamed , Rashid Harunur , Burrows Peter D , Bridges Louis S , Javed Amjad , Schroeder Harry 
Published: January 2023

Abstract
There are strong indications that B lineage cells play a key role in bone homeostasis. The preB cell receptor is composed of an immunoglobulin mu H chain, VpreB and immunoglobulin λ5. Young λ5 deficient mice have reduced numbers of preB cells and mature B cells, moreover; their bone appears to be normal. With time, they achieve normal numbers of mature B cells while exhibiting major bone loss. To test whether expression of λ5 is playing a critical role maintaining bone homeostasis, we evaluated bone in: mice lacking immunoglobulin JH (JH −/− λ5+/+). These mice lack both preB and mature B cells, but maintain expression of λ5 in progenitor B cells. Mice deficient in both JH and λ5 (JH −/− λ5−/−) have no preB or mature B cells, and also no λ5. Using both μCT and histologic evaluation, we compared femur and skull at six months of age in these three mutant strains to normal controls. JH −/− λ5+/+ femur and skull were similar to WT. Both JH +/+λ5−/− and JH −/− λ5−/− mice showed significant decrease in femoral trabecular bone and increased loss of skull bone. Irradiated WT mice transplanted with JH −/− λ5−/− bone marrow cells developed defective femoral and cranial bones. In contrast, JH −/−λ5−/− mice that received WT bone marrow cells recovered bone architecture. In vitro culture of bone progenitors from JH +/+λ5−/− and JH −/− λ5−/− mice showed decreased ability of bone formation. These data underscore the importance of immunoglobulin λ5 in skeletal development.
The aged thymus is impaired in supporting T cell central tolerance
Authors: Lancaster Jessica N , Srinivasan Jayashree , Selden Hilary J. , Nam Seohee , Ehrlich Lauren Ilyse Richie 
Published: January 2023

Abstract
During aging, the thymus undergoes involution, decreasing dramatically in size and mass, and becoming increasingly disorganized. Notably, thymic epithelial cells decline with age, especially within the compartment of mature medullary thymic epithelial cells (mTECs) that express and present tissue-restricted antigens to thymocytes. Age-associated changes in the composition of hematopoietic antigen-presenting cells (APCs) have also been observed, but are not well characterized. Given that both mTECs and APCs present diverse self-antigens to thymocytes, we hypothesized that central tolerance is impaired in the aged thymus. Using live-cell two-photon microscopy, we determined that CD4-single positive (CD4SP) thymocytes, regardless of thymocyte age, had reduced motility and accumulation within the medulla of an aged thymus. We report age-associated changes in both the localization and composition of thymic APC subsets. To test whether this altered thymic environment functionally impacted central tolerance, we used thymic slice assays to measure tolerance induction of CD8− and CD4SP thymocytes encountering a range of model self-antigens. These assays indicated that central tolerance in the aged thymus was impaired, particularly against low-avidity auto-antigens. Our findings indicate that newly generated T cells selected in an aged thymic environment have not undergone a rigorous screening process against autoimmunity.
Histone Deacetylase 3 controls lung alveolar macrophage development and homeostasis by regulation of PPAR-γ expression through deacetylating PU.1
Authors: Yao Yi , Liu Queping , Adrianto Indra , Yin Congcong , Geissmann Frederic , Zhou Li , Mi Qing-Sheng 
Published: January 2023

Abstract
Alveolar macrophages (AMs) are derived from embryonic precursors that seed the lung before birth and self-maintain locally throughout adulthood but can be regenerated by bone marrow (BM) under stress conditions. However, how to precisely regulate AM development still remains unknown. Here we report that histone deacetylase 3 (HDAC3) is a key epigenetic factor required for AM embryonic development, postnatal homeostasis, maturation, and regeneration from BM. Loss of HDAC3 in early embryonic development affects AM development starting at E14.5, while loss of HDAC3 after birth affects AM homeostasis and maturation. HDAC3-deficient AMs exhibit severe mitochondrial oxidative dysfunction and deteriorative cell death. Single-cell RNA sequencing analyses further identified four distinct AM sub-clusters and a lack of HDAC3 dysregulated AM transcriptome in a cluster-specific manner. Mechanistically, HDAC3 serves as a co-activator via deacetylation of PU.1 to promote Pparg transcription. Our findings identify HDAC3 as a key epigenetic regulator of lung AM development and homeostasis.
Siglec-F-negative resident eosinophils represent an unexpectedly dominant population in homeostatic murine bone marrow
Authors: Jeong Brian M , Walker Matthew , Coden Mackenzie , Nam Kiwon , Nagasaka Reina , Abdala-Valencia Hiam , Berdnikovs Sergejs 
Published: January 2023

Abstract
Bone marrow, while known to be a hematopoietic site for eosinophils, also harbors resident populations of these cells. Identification of such resident eosinophils typically requires flow cytometry-assisted sorting, with Siglec-F as a key marker for identification of murine eosinophils. At baseline, we found that bone marrow resident eosinophils described as Siglec-F(+) constitute about 5% of CD45 cells. Although this identifies mature eosinophils, it may not be sufficient to represent all resident phenotypes. Using sequencing and FACS sorting approaches, we found that the Siglec-F(+) population represented only a minority of the resident eosinophil pool. Rather, we identified a lineage-positive population of IL-5Ra(+)Ly6G(+) but Siglec-F(−) cells distinct from lineage-negative EoPs (eosinophil progenitors). At 40% of all CD45(+) hematopoietic cells in adult mice, this bone marrow resident population dwarfs the Siglec-F(+) eosinophil pool. When sorted from bone marrow homogenates and treated with IL-5, these resident cells acquired all characteristics of mature eosinophils, including expression of Siglec-F and granular proteins (EPX, MPO). These tissue residents may play critical homeostatic roles in normal murine bone marrow and should be accounted for in studies of eosinophil biology.
IL7R regulates fetal tissue resident macrophage development by facilitating cell survival
Authors: Leung Gabriel , Valencia Clint , Beaudin Anna 
Published: January 2023

Abstract
Tissue-resident macrophages (TRMs) play critical roles in tissue homeostasis and disease. Many populations of TRMs derive from fetal progenitors and independently self-maintain across the lifespan through in situ proliferation. Previously, we have identified the interleukin-7 receptor (IL7R) as a novel regulator of TRM development. We have shown that antibody blockade of the IL7R during gestation impaired liver, lung, and epidermal TRM cellularity at birth. Here we show that in vivo fetal rIL-7 stimulation of the IL7R increased neonatal liver and lung TRM. In order to determine how IL7R signaling regulates fetal macrophage development, apoptosis was measured after late gestation IL7R blockade. Apoptosis in the macrophages and monocytes of the liver and lung was dramatically increased after IL7R blockade, suggesting that increases in neonatal cellularity after rIL-7 treatment may be due to increased survival signaling in these tissues. Our previous analysis also revealed dynamic regulation of IL7R mRNA surface protein expression as fetal monocytes differentiate into CD64+ macrophages during fetal development. We performed intracellular staining for IL7Ra protein to determine that monocytes contain intracellular IL7R protein that is not expressed on the surface until differentiation, suggesting that regulation of IL7R expression occurs at the level of surface expression. These data reveal dynamic regulation of IL7Ra expression in TRMs and TRM precursors during late gestation and provide evidence that IL-7/IL7R signaling regulates fetal TRM development by facilitating cell survival. Ongoing work addresses downstream signaling and other developmental processes regulated by IL7R signaling during fetal TRM development.
Cannabidiol alters macrophage differentiation resulting in accumulation of immunosuppressive myeloid cells and dendritic cells
Authors: Miranda Kathryn , Culpepper Courtney , Wilson Kiesha , Nagarkatti Prakash S. , Nagarkatti Mitzi 
Published: January 2023

Abstract
Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has anti-inflammatory properties; however the precise immunological mechanisms involved are not clear. Research from our laboratory has established that CBD promotes expansion of immunosuppressive myeloid-derived suppressor cells (MDSC), which are immature leukocytes thought to have stalled their differentiation towards mature myeloid lineages such as macrophages and dendritic cells (DC). In the current study, we aimed to better understand the mechanisms of CBD-altered hematopoiesis. We performed flow cytometry and single cell RNA sequencing (sc-RNAseq) on peritoneal cells from C57BL/6 mice treated with Vehicle (Veh) or CBD (20mg/kg, i.p.). Consistent with our previous studies, CBD promoted accumulation of MDSCs after 24h, which dissipated after 48h. Strikingly, MDSC accumulation was preceded by ablation of macrophages, which was maintained beyond 48h. In addition, accumulation of DCs started at 12h and accelerated through 48h. Similarly, sc-RNAseq of peritoneal cells harvested at 24h showed two distinct populations of cells expressing Adgre1, which encodes F4/80. These two clusters were distinct between Veh- and CBD-treated mice due to their drastically altered transcriptomes. The Veh-distinct cluster was comprised of macrophages expressing complement genes, while the CBD-distinct cluster was comprised of MDSCs expressing Arg1. Furthermore, the DC cluster expressing Ccr2 was enlarged in CBD-treated mice. Together, our results demonstrate that CBD drastically alters hematopoiesis, depleting macrophages and promoting MDSCs and DCs. These findings suggest CBD treatment may be beneficial in various macrophage-driven inflammatory disorders.
Inflammasome driven cell death in response to DNA damage is required for normal brain development and function
Authors: Lammert Catherine Rose , Lukens John R 
Published: January 2023

Abstract
Neurodevelopment is characterized by rapid rates of neural cell proliferation and differentiation followed by a period of massive cell death where over half of all recently generated brain cells are removed. Large amounts of DNA damage, cellular debris, and byproducts of cellular stress are generated during these neurodevelopmental events, all of which can potentially activate immune signaling. How the immune response to this damage influences brain maturation and function currently remains poorly understood. Here we show that the AIM2 inflammasome contributes to proper brain development and that disruptions in this immune sensor of genotoxic stress lead to behavioral abnormalities. We find that neurodevelopment is characterized by pronounced AIM2 inflammasome activation and that defects in this DNA damage surveillance sensor result in anxiety-related behaviors. We show that the AIM2 inflammasome contributes to CNS homeostasis specifically through its regulation of the cell death executioner Gasdermin-D, and not via its involvement in IL-1/IL-18 production. Consistent with a role for this dsDNA sensor in the purging of genetically compromised central nervous system cells, we find that defective AIM2 inflammasome signaling results in decreased neural cell death both in response to DNA damage-inducing agents and during neurodevelopment. Moreover, we report that disruptions in DNA damage surveillance by the AIM2 inflammasome lead to excessive DNA damage accumulation in neurons as well as increased numbers of neurons that incorporate into the adult brain. Our findings identify the inflammasome as a critical player in establishing a properly formed CNS through its role in the removal of genetically compromised cells.
Role of CD137L in lumbar spinal cord microglial responses following sciatic nerve crush
Authors: OHARA KINUYO , Nicholas David , Cao Ling 
Published: January 2023

Abstract
Neuropathic pain is one of the most devastating kinds of chronic pain, which is still largely treated sub-optimally in part due to incomplete understanding. Using murine sciatic nerve crush (SNC) model, we have shown that spinal cord CD137 ligand (CD137L; AKA 4-1BBL) contributes to the development of SNC-induced pain-like behaviors and functional recovery following SNC. Here, we further investigated the potential involvement of lumbar spinal cord microglial responses in CD137L-mediated behavioral changes following SNC. Mononuclear cells were isolated from lumbar spinal cords of both wild type (WT) B6 and B6_CD137L knockout (KO) mice via Percoll gradient followed by flow cytometric analysis at days 0 (naïve), 3, 7, 14, 28 and 56 following SNC or sham surgery. Microglia were identified as CD45lowCD11b+ populations. In WT mice, the total number of microglia peaked at day 14 and then gradually reduced following SNC. The increase of microglial numbers was minimal in all other groups compared to the WT SNC mice. Similar pattern of changes were also observed with the numbers of CD86+ microglia (pro-inflammatory phenotype) and CD206+ microglia (anti-inflammatory phenotype), however the numbers of CD206+ microglia were much less. Our results support the notion that reduced lumbar spinal cord microglial responses contributes to the reduction of pain-like behaviors and improved functional recovery in CD137L deficient mice. CD137L-mediated microglial responses will be further investigated to elucidate the role of spinal cord CD137L in the development of neuropathic pain. (Supported by NIH/NINDS R01NS098426 (Cao))
α-Synuclein-specific T cell reactivity is associated with preclinical and early Parkinson’s disease
Authors: Arlehamn Cecilia S Lindestam , Dhanwani Rekha , Pham John , Kuan Rebecca , Frazier April , Dutra Juliana Rezende , Phillips Elizabeth J , Mallal Simon Alexander , Roederer Mario , Marder Karen S , Amara Amy W , Standaert David G , Goldman Jennifer G , Litvan Irene , Peters Bjoern , Sulzer David , Sette Alessandro 
Published: January 2023

Abstract
A clinical diagnosis of motor Parkinson’s disease (PD) is preceded by a prolonged premotor phase with accumulating neuronal damage. α-Synuclein (α-syn)-specific T cell reactivity is preferentially associated with PD patients. Here we examined the temporal relation between α-syn T cell reactivity and PD. Analysis of PBMCs from a longitudinal case study revealed that elevated α-syn-specific T cell responses were detected prior to the diagnosis of motor PD, and declined after. These results suggest that α-syn-specific proinflammatory T cell reactivity could serve as an early predictor of PD. The relationship between T cell reactivity and early PD was further examined in two independent cohorts, which showed that α-syn-specific T cell responses were highest shortly after diagnosis of motor PD and then decreased. Additional analysis of clinical variables revealed significant association of α-syn-specific T cell responses with age and lower levodopa equivalent dose, and no correlation with motor and cognitive deficits. These results confirm the presence of α-syn-reactive T cells in PD and show that they are most abundant immediately after diagnosis of motor PD. Our single case study suggests that these cells may be present years before the diagnosis of motor PD, suggesting new avenues of investigation into PD pathogenesis, potential early diagnosis, and treatment options.
Conventional DC specific CSF1R depletion represents the reduction of the alveolar cDC2 and attenuation of allergic lung inflammation
Authors: Moon Hyung-Geun , Kim Seung-Jae , Park Gye Young 
Published: January 2023

Abstract
Dendritic cells play a key role in sensing aeroallergen and initiating Th2 immune reaction in asthma by bridging between innate and adaptive immune responses. Among the DC subtypes, conventional DC2 (cDC2) has been known to be a major player in developing allergic asthma. We recently reported that airway epithelial cell-derived CSF1 significantly promotes allergic sensitization through activating alveolar CSF1R+ cDC2 resulting in enhanced allergen-specific IgE production and subsequent Th2 immune response. This finding highlights the fundamental role of cDC2 in allergen sensitization. However, studying cDC2 has been hindered by the lack of available cDC2 specific-Cre mouse. Since CSF1R promoter activity is relatively enhanced in cDC2, we generated Zbtb46-cre;Csf1rfl/fl mice (hereafter CSF1RΔcDC) by crossbreeding cDC specific Zbtb46-cre and CSF1R flox mice. Of interest, we found that CSF1RΔcDC has a significant reduction in cDC2 population in alveolar space compared to Zbtb46-cre mice, whereas cDC1 and cDC2 in the lung and cDC1 in alveolar space were not affected in the steady state. When the mice were subjected to the allergen challenge, the number of cDC2 migrating to regional lymph node with carrying the allergen was markedly diminished in CSF1RΔcDC mice. Subsequently, the production of total and allergen-reactive IgE was blocked and allergic lung inflammation including eosinophil recruitment was attenuated in CSF1RΔcDC mice, compared to control littermate mice. These data suggest that CSF1RΔcDC mice are suitable to investigate the specific role of cDC2 in alveolar space and CSF1R+ cDC2 in alveolar space plays a key role in allergen sensitization and asthma development.
The role of IL-9 secreting CD4+ T helper cells in promoting mast cell expansion in pulmonary models of inflammation
Authors: Pajulas Abigail , Kaplan Mark H 
Published: January 2023

Abstract
Mast cells are tissue resident cells with granules that contain histamine and other proinflammatory mediators. Mast cells are important effectors in immediate type I hypersensitivity reactions. In severe allergic reactions, immunoglobulin E (IgE)-mediated mast cell degranulation triggers localized and systemic anaphylaxis. In allergic asthma, mast cells and T cells interact in the generation of long-lasting inflammation. The molecular mechanisms responsible for mast cell expansion has not been fully elucidated. Because T cells are an important source of the mast cell growth factor IL-9, we are interested in understanding the role of IL-9, and IL-9-producing T cells in mast cell expansion and recruitment. We have identified a role of T helper 9 (Th9) cells in influencing mast cell number and function in pulmonary models of inflammation. Using adoptive transfer models, we have defined a contribution of Th9 cells in immediate hypersensitivity. We have demonstrated that IL-9 expands mast cell progenitor numbers in bone marrow and lung, suggesting that there are systemic effects of local IL-9 production. We hypothesize that increased mature mast cells in the pulmonary system are from recruitment and expansion of progenitor cells rather than expansion of mature cells in situ. Ongoing studies will directly examine the relative contribution and function of the two populations during models of allergic airway inflammation.
Therapeutic approach to steroid-resistant asthma
Authors: Mori Akio , Kouyama Satoshi , Yamaguchi Miyako , Kumitani Chiemi , Ohtomo-Abe Akemi , Fujita Norihiko , Iwata Maki , Nagayama Kisako , Ryu Kai , Nakamura Yuto , Hamada Yuto , Hayashi Hiroaki , Watai Kentaro , Kamide Yosuke , Sekiya Kiyoshi , Fukutomi Yuma , Taniguchi Masami , Ohtomo Takayuki , Kaminuma Osamu 
Published: January 2023

Abstract

Background
To control therapy-resistant eosinophilia, synergistic effects of CTLA4-Ig and glucocorticoid was investigated on T cell-induced asthma model.

Methods
Ovalbumin (OVA) specific murine helper T cell (Th) clones were established from DO11.10 transgenic mice. To analyze steroid responsiveness in vitro, Th clones were cultured with antigen presenting cells and OVA in the presence of various concentration of dexamethasone (DEX). Proliferative responses were measured by incorporation of either 3H-thymidine or BrdU. For in vivo analysis, unprimed Balb/c mice were transferred with Th clones, challenged with OVA, and administered with DEX subcutaneously. CTLA4-Ig was administered intravenously. BALF was obtained 48 hours after the challenge, and the number of infiltrating cells was differentially counted.

Results
Steroid-sensitive (SS) and -resistant (SR) clones were selected based on the effect of DEX on the proliferative responses of antigen-stimulated Th clones. Airway infiltration of eosinophils of mice transferred with SS clones were effectively inhibited by the administration of DEX. In contrast, those of mice transferred with SR clones were not significantly inhibited by DEX. Addition of CTLA4-Ig into the culture significantly suppressed the proliferation of DEX-treated SR clones in vitro. Administration of CTLA4-Ig significantly suppressed eosinophil infiltration of SR asthma model transferred with SR clones in vivo. CTLA4-Ig and DEX synergistically suppressed in vitro proliferation of SS clones and in vivo BALF eosinophilia of mice transferred with SS clones.

Conclusion
Blocking costimulatory signal mediated through CD28 is a promising target to treat therapy-resistant eosinophilia.