bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of innate lymphoid cells in the heart and cardiac inflammation
Authors: Choi Hee Sun , Hou Xuezhou , Bracamonte-Baran William , Diny Nicola , Talor Monica , Cihakova Daniela 
Published: January 2023

Abstract
Studies have shown the diverse role of innate lymphoid cells (ILCs) in mucosal organs, however, the role of ILCs in the heart has not been studied. The aim of the work was to examine the role of group 2 innate lymphoid cells (ILC2s) in the heart and inflammatory heart diseases. To study the role of ILCs in the heart, we used a pericarditis model where IL-33 treatment induces pericarditis in mice. In this model, diastolic dysfunction was observed in the heart of IL-33-treated mice and eosinophils were heavily infiltrated into the heart. We found that the number of ILC2s was increased in the heart after IL-33 administration. We hypothesized that IL-33 induces cardiac ILC2s to produce IL-5 and IL-13, which drives pericarditis development. To examine whether ILCs are required for pericarditis development, we treated WT, Rag2−/− and Rag2−/−γc−/− mice with IL-33. Rag2−/−γc−/− mice which are deficient in all lymphoid cells including ILCs were completely protected from developing pericarditis, while WT and Rag2−/− mice developed pericarditis, indicating the adaptive immunity is not required for the development of IL-33-induced pericarditis. This data suggests that ILCs might play a pathogenic role in the heart. To determine the function of ILC2s, we analyzed cytokine production by ILC2s in the heart. Cardiac ILC2s were a major producer of IL-5 and IL-13. With anti-IL-5 treatment, the number of eosinophils in the heart was reduced, which prevented the heart from developing pericarditis. IL-13−/− mice showed less severe pericarditis upon IL-33 treatment than WT mice. Collectively, our data suggest that ILCs play a critical role in pericarditis, and could provide insight into novel strategies for treating this disease.
IL-17A induced hematopoietic reprogramming produces both PMN and MDSC at the post-acute stage of inflammation.
Authors: Culpepper Courtney D. , Tremblay Alexandra V. , Bian Zhen , Niu Shuo , Liu Yuan 
Published: January 2023

Abstract
Our previous study suggests that polymorphonuclear leukocyte (PMN) response is enhanced at the post-acute stage of murine colitis due to changes in bone marrow (BM) myelopoiesis. Herein, we report that hematopoietic reprogramming during the post-acute phase of inflammation produces myeloid derived suppressor cells (MDSC) that co-infiltrate the intestine with PMN. Employing Percoll density gradients, we analyzed dynamic changes to the myeloid compartment by separating BM leukocytes from DSS colitis-to-recovery mice into four density-increasing bands with myeloid leukocytes enriched in bands III (50–60%) and IV (60–70%). Band III was comprised of monocytes and low-density granulocytes; both confirmed to be M-MDSCs and G-MDSCs, respectively, by displaying potent inhibition of T-cell proliferation. Despite significant decreases in the PMN population, presumably caused by mobilization into inflamed tissues, MDSC numbers significantly increase beginning at the post-acute stage of colitis. Furthermore, MDSC numbers do not return to baseline until late in the recovery stage. The expanded G-MDSCs also showed increased CXCR2 expression, which guides egress out of BM, and produced ROS upon PMA activation. Adoptive transfer assays demonstrated that functionally enhanced PMN infiltrated the intestine at the post-acute stage to clear the existing inflammatory reaction, while MDSC accumulated in the intestine during recovery suggesting a role in tissue repair. IL-17A signaling at the post-acute stage of inflammation likely induced hematopoietic reprogramming of the myeloid compartment, as its neutralization blocked expansion and infiltration of both PMN and MDSC.
Loss of MSP-dependent Ron receptor signaling exacerbates liver fibrosis in a high fat high cholesterol diet-induced ApoE KO mouse model
Authors: Allen Joselyn Natasha , Kennett Mary , Patterson Andrew , Hankey-Giblin Pamela A. 
Published: January 2023

Abstract
Liver fibrosis marks the turning point of non-alcoholic steatohepatitis and with no specific and effective anti-fibrotic therapies available, this disease is a major global health burden. Here, we established the novel role of the Ron receptor in mitigating liver fibrosis. For 18 weeks, apolipoprotein E (ApoE KO) and ApoE x Ron double knockout (DKO) mice were fed a fat and cholesterol-rich diet. Livers from DKO animals exhibited increased accumulation of sirius red-stained collagen. Immunohistochemistry of αSMA revealed that DKO livers had increased activation of collagen-producing hepatic stellate cells. In agreement with this, DKO livers exhibited higher expression of pro-fibrogenic molecules, PDGF, CTGF, and TGFβ. Additionally, DKO mice exhibited increased hepatic expression of collagens (Types 1, 3, and 4) and ECM remodeling proteins (MMP-2 and TIMP-1). The expression of pro-fibrogenic inflammatory cytokines (TNFα and IL-12b), receptors (TLR-4), and chemokines (MIP-2, CCL2, and CCL5) were significantly higher in DKO livers. DKO livers also exhibited increased infiltration of F4/80+ Kupffer cells, which are well-known to mediate the majority of cytokine and chemokine expression in fibrotic livers. Ron also attenuated several risk factors of liver fibrosis including insulin resistance, steatosis, hepatocellular damage, and inflammation. Despite lifestyle changes and pharmacotherapies for treating etiologies of liver fibrosis, the disrupted liver homeostasis often remains and requires effective treatments. Investigating the protective functions of Ron offers a pharmacological target for resolving the steatohepatitis spectrum.
Regulators of mycobacterial granuloma formation – CCL2 and VEGF-A
Authors: Herbath Melinda , Harding Jeffrey S. , Marcus Sarah , Hasko George , Nagy Andras , Fabry Zsuzsanna , Sandor Matyas 
Published: January 2023

Abstract
Granulomas are macrophage dominated lesions and are a central feature of mycobacterial infections. These cell aggregates are dynamically changing structures as the life span of the granuloma recruited effector cells is relatively short and the cells have to be replaced. CCL2 and VEGF-A are required for granuloma maintenance as blocking the action of these chemokines results in reduction of granuloma size and number after BCG or Mtb infections. We seek to elucidate the relevance of these two cytokines in the timeline of mycobacterial infections and their relative contribution to granuloma formation. CD11c+ cell immigration is impaired, costimulatory molecule expression is lower and granulomas are smaller while the bacterial burden is higher in the liver when CCR2KO mice are infected i.p. with M. bovis BCG. Similarly, in animals that are selectively deficient in macrophage VEGF-A production the granulomas are smaller.
Granuloma cells produce VEGF-A. Caseating granulomas, like the ones induced in C3HeB/FeJ (Kramnik) mice are hypoxic and hypoxia is a strong inducer of VEGF-A production. Sarcoid lesions induced by BCG or Mtb in B6 mice are not hypoxic but we show that ATP released from dead cells induces VEGF-A in a subpopulation of macrophages in the granulomas.
Additionally, VEGF production proved to be dependent on granuloma size: bigger granulomas produce larger quantities of VEGF-A while smaller lesions produce less or none. This finding suggests that unlike other chemokines such as CCL2, which is described to be involved in both granuloma initiation and maintenance, VEGF-A may support an increased lesion size in the late acute phase of infection.
Regulating cellular recruitment may provide new therapies for granulomatous diseases.
Using Multiplex and Single-Molecule Bead-Based Technologies to Assess Inflammatory Changes Following Skeletal Muscle Injury
Authors: McFarlin Brian Keith , Bowman Erin M. , Gary Melody A. , Stelly Steven , Tanner Elizabeth A. , Davis Asheal 
Published: January 2023

Abstract
Inflammation is a key component in the healing and recovery of injured skeletal muscle. Despite the known importance of inflammation, its response has not been consistently demonstrated in human experimental model systems. One plausible explanation for the inconsistent outcomes in human skeletal muscle injury models may be caused by the analytical methods selected. Traditional methods (i.e. ELISA, Western Blotting, etc.) used to measure serum inflammatory/muscle damage biomarkers lack the bandwidth and/or sensitivity to measure multiple biomarkers or femtomolar changes. The purpose of this investigation was to describe a comprehensive method for the measurement of serum inflammatory biomarkers in a human skeletal muscle injury model. To accomplish this objective, we combined 384-well, bead-based multiplex assays (MILLIPLEX® and Luminex® FM3D) with a novel, bead-based single molecule detection technology (MilliporeSigma SMCxPro). The samples used in the present investigation were collected from an IRB-approved study and consented subjects (in accordance with the latest Declaration of Helsinki). Subjects completed a muscle damage exercise session and blood samples were collected at 0, 24, 48, and 72-h after muscle damage. We observed a significant change in inflammation post-damage using both detection technologies. Combining multiplexing with the precise, single molecule counting detection method allowed for a better clarification and description of the inflammatory response in otherwise undetectable sample concentrations. More research is needed to demonstrate repeatability for this assay approach as well as validation for other inflammatory states (i.e. chronic inflammatory disease).
Neutrophil extracellular traps are a heterogeneous feature in sickle cell disease
Authors: Barbu Emilia Alina , Dominical Venina M. , Mendelsohn Laurel , Thein Swee Lay 
Published: January 2023

Abstract
Sickle cell disease (SCD) is an inherited hemoglobin disorder caused by a single base change (A-T) in the beta-globin gene of hemoglobin with ensuing recurring inflammation that results in progressive end-organ damage and early mortality. Production of neutrophil extracellular traps (NETs) have been shown to be a key component of this inflammatory process in SCD pathophysiology.
We sought to determine the relevance of NETosis versus a different type of programmed cell death (apoptosis) in SCD. We used an indirect assay using healthy neutrophils exposed to paired plasma samples (n=16) from SCD patients in steady-state and crisis for 30 min to 7 hrs, and a direct approach of observing neutrophils (3 healthy and 3 SCD) themselves up to 4 hrs. Features of NETosis (histone citrullination, nuclear decondensation, string nets) and apoptosis (piknotic nuclei, c-Parp, membrane damage) were assessed by imaging flow cytometry and fluorescence microscopy. Additionally, plasma titers for 20 inflammatory analytes were determined for the 16 paired SCD samples and 4 healthy controls. High circulating IL-6 levels at crisis found in 9/16 of the paired samples correlated with an increased number of NETs at crisis compared to steady-state. NETs were also observed directly in SCD neutrophils at steady state but not consistently. When NETs or histone citrullination were absent or low, c-Parp was typically detected. Additionally, membrane damage was observed in neutrophils from all SCD donors. The data suggest that the SCD environment disrupts neutrophil homeostasis and activate multiple cell death programs. SCD NETosis appears to be heterogeneous, its contribution to the disease pathophysiology remains to be determined.
Accelerated onset of arthritis by systemic infection of Mycoplasma fermentans in the knock-in mice gp130F759
Authors: YAHAGI Ayano , SAIKA Taro , HIRANO Hiroyasu , ISEKI Masanori , ISHIHARA Katsuhiko 
Published: January 2023

Abstract
Development of autoimmune diseases is influenced by both genetic and environmental factors. The knock-in mouse gp130F759 having a point mutation Y759F in gp130, a signaling receptor subunit for IL-6 family cytokines, spontaneously develops arthritis like rheumatoid arthritis (RA) at 8 months old (M.O.) by aberrant IL-6 signals. Mycoplasma fermentans (Mf) was reported to exist in the synovial fluid of RA, but its pathogenic role has not been clarified. In this study, we examined the effects of systemic infection with Mf on the arthritis of gp130F759, and the cellular changes in the synovium. Gp130F759 at 3 M.O. with no symptoms of arthritis were infected with Mf via vein. The clinical scores based on the restriction of joint flexibility were determined from day 3 to 28 after infection. At 1 month after infection, the group with Mf infection had significantly higher total scores of 4 limbs than the group at the same age without infection. Additionally, the cellular populations and numbers in the synovium were analyzed with flowcytometry. The kinetics study revealed that the numbers of the synovial cells predominated by neutrophils increased at day 10 and 28 after infection. To verify the roles for neutrophils increased, 0.25 mg of anti-Gr-1 antibody was injected intraperitoneally at 9 days after infection. The group of treated mice showed no increases of the clinical scores and the synovial cells at 1 month after infection. These data indicated that systemic infection of Mf induces neutrophil-dependent facilitation of arthritis in gp130F759. We propose that this model is useful to clarify the molecular events caused by microorganisms at the preclinical phase of RA.
Signal crosstalk between cytokine RANKL and AhR signaling in osteoclasts controls bone homeostasis
Authors: Izawa Takashi , Arakaki Rieko , Tanaka Eiji , Ishimaru Naozumi 
Published: January 2023

Abstract
The nuclear receptor aryl hydrocarbon receptor (AhR) plays a crucial role in receptor activator of nuclear factor (NF)-kB ligand (RANKL)-mediated osteoclastogenesis. A considerable amount of evidence reveals that AhR is also a key modulator of skeletal remodeling. However, the mechanism underlying the regulation of AhR expression in osteoclasts and the signaling pathway through which AhR controls osteoclastogenesis remain unclear. We found that the expression of AhR in bone marrow-derived osteoclasts was upregulated by RANKL at an earlier stage than the expression of signature osteoclast genes such as NFATc1, c-Src, integrin avb3, and cathepsin K. In response to RANKL, bone marrow macrophages isolated from AhR−/− mice exhibited impaired phosphorylation of Akt and mitogen-activated protein kinase as well as NF-kB, while their response to the macrophage colony-stimulating factor remained unchanged. Osteoclast differentiation mediated by the AhR signaling pathway was also regulated in a RANKL/c-Fos-dependent manner. Further, ligand activation of AhR by the smoke toxin benzo [a] pyrene (BaP) accelerated osteoclast differentiation in a receptor-dependent manner, and AhR-dependent regulation of mitochondrial biogenesis in osteoclasts was observed. Moreover, AhR−/− mice exhibited impaired bone healing with delayed endochondral ossification. Taken together, the present results suggest the new role that the RANKL-AhR-c-Fos signaling axis plays a critical role in osteoclastogenesis, thereby identifying the potential of AhR in treating pathological, inflammatory, or metabolic disorders of the bone.
C-C motif chemokine receptor 2 drives protective immunity by mediating alveolar macrophage localization in tuberculosis granulomas
Authors: Dunlap Micah , Howard Nicole , Das Shibali , Ahmed Mushtaq , Prince Oliver , Rangel-Moreno Javier , Rosa Bruce , Mitreva Makedonka , Randolph Gwendalyn J. , Khader Shabaana 
Published: January 2023

Abstract
C-C motif chemokine receptor 2 (CCR2) axis is a major chemokine axis that recruits myeloid cells including monocytes and macrophages. Thus far, CCR2−/− mice have not been found to be more susceptible to infection with Euro-American lineage 4 strains of Mycobacterium tuberculosis (Mtb). Here, using a prototype W-Beijing family lineage 2 clinical Mtb strain, HN878, we show that CCR2−/− mice exhibit increased susceptibility to tuberculosis (TB). Following exposure to Mtb HN878, alveolar macrophages (AMs) are amongst the earliest cells infected. Using a novel labeling technique, we show that AMs accumulate early in the airways following Mtb HN878 infection and express CCR2. During disease progression, CCR2-expressing AMs exit the airways and localize within the TB granulomas to mediate protective immunity. RNA-sequencing of sorted airway and non-airway AMs show distinct gene expression profiles, suggesting that upon exit from airways, AMs become classically activated. Furthermore, absence of CCR2+ cells specifically at the time of AM egress from the airways resulted in enhanced susceptibility to Mtb infection, increased accumulation of neutrophils, and loss of Mtb control. Interestingly, we provide new evidence that infection with an Mtb strain HN878 mutant lacking phenolic glycolipid (PGL) expression still resulted in increased susceptibility in CCR2−/− mice. Together, our data provide novel evidence for a critical protective role for CCR2 in AM localization within the TB granulomas to mediate protective immunity against clinically relevant and emerging Mtb infections.
The P2Y purinoceptor, P2Y14R, promotes AHR in an animal model of asthma
Authors: Karcz Tadeusz , Nakano Hideki , Jacobson Kenneth , Cook Donald 
Published: January 2023

Abstract
The initiation and propagation of immune responses in the lung are mediated in part by so-called ‘alarmins’ that include nucleotides and nucleotide-sugars. Uridine diphosphate (UDP), and UDP-sugars, such as UDP-glucose (UDP-Glc) can be released by airway epithelial cells and bind to the G-protein coupled receptor, P2Y14R on leukocytes. However, the role of these molecules in allergic airway inflammation remains unclear. Our analysis of flow cytometry sorted cells from the lung revealed that P2ry14, the gene encoding P2Y14R, is primarily expressed in alveolar macrophages and in CD103+ dendritic cells. Using P2Y14R-specific agonists and antagonists, we tested whether this receptor has a role in allergic airway disease. Although we found no evidence that UDP-glucose or P2Y14R were involved in allergic sensitization through the airway, administration of UDP-Glc or agonists of P2Y14R during the allergen challenge phase acted synergistically with the inhaled allergen to promote neutrophilic inflammation. Conversely, administration of the P2Y14R antagonist, PPTN, during the challenge phase attenuated inflammation. To exclude the possibility that these results stemmed from non-specific effects or cell toxicity, we studied P2ry14-deficient mice. Compared to WT animals, P2ry14-deficient mice displayed significantly less airway hyperresponsiveness following allergen challenge. Together, these results suggest that existing antagonists of P2Y14R, or their derivatives, might be useful to control asthma exacerbations in humans.
IL33 signaling contributes to diesel exhaust particles-induced asthma exacerbations by promoting innate and adaptive type 2 and type 17 responses
Authors: Brandt Eric B. , Bolcas Paige E. , Ruff Brandy P. , Khurana Hershey Gurjit K. 
Published: January 2023

Abstract

Rationale
Exposure to traffic pollution, notably diesel exhaust particles (DEP), promote asthma exacerbations and a mixed Th2/Th17 response. The contribution of TSLP and IL33, generated by sressed lung epithelial cells, to DEP-induced asthma exacerbations remains poorly understood.

Method
We used TSLP receptor deficient mice, mice lacking the IL33 receptor (ST2) and Balb/c control mice and exposed them 9 times over a 3-week period to saline, house dust mite extract (HDM; 10ug) and/or DEP (100ug). Seven weeks later some mice received a single HDM challenge to assess memory responses. Airway hyper-responsiveness (AHR), BALF inflammation and lung T-cells and ILC subsets were assessed after primary and recall responses.

Results
DEP co-exposure with HDM exacerbates HDM-induced AHR and Th2 responses. AHR was similar between TSLPR deficient mice and control mice exposed to HDM+DEP. In contrast, AHR was significantly decreased in ST2-deficient mice compared to wild type mice. The impact of ST2 deficiency on lung accumulation of ILC2 and Th2 cells was modest. Following HDM+DEP co-exposures, decreases in ILC3, γδ T-cells and Th17 cells were observed in the lungs of ST2 deficient mice compared to control mice. The in vivo HDM recall response recapitulated the impaired AHR associated with decreases in IL17A secreting cells observed after the primary response in HDM+DEP exposed ST2 deficient mice. Finally, a decrease in lung levels of pathogenic IL5/IL13/IL17A producing CD4+ T-cells was observed after the primary and recall responses.

Conclusions
IL33 but not TSLP contributes to DEP-induced asthma exacerbations by affecting the accumulation of innate and adaptive type 2 and type 17 cells, notably pathogenic Th2/Th17 cells.
miR-396 ameliorate allergic inflammation in a mouse model of asthma
Authors: Shen Chao-Bin , Yu Lan , Wang Song 
Published: January 2023

Abstract

Aim of the Study
Astragalus root has good properties in enhancing immune function as well as preventing and treating disease. In previous ours study, Next-generation sequencing identified miR-396 as the most abundant plant microRNA expressed in Astragalus root. We investigated the effects of an synthetic miR-396 mimics and its mechanism of action in a mouse model of acute bronchial asthma.

Materials and Methods
BALB/c mice were sensitized and challenged with ovalbumin (OVA). The functional role of miR-396 was assessed by using in silico analysis. The miR-396 mimics was administered by intranasal instillation from the day of challenges every 2 days. HE staining was used to observe the pathological changes of the lung tissue, and expression levels of miR-396 mimics in lung tissues, serums, and spleen were analyzed by RT-PCR. The transcription factors mRNA were determined by RT-PCR in mouse model with asthma and control groups in splenocytes.

Results
GATA-3 of mRNA was significantly down-regulated in asthma model of mice treated with miR-396 mimics in splenocytes. The miR-396 mimics also suppressed STAT-6 and ROR-γt of mRNA compared with that of the OVA-challenged groups. The levels of transcription factors involved in the Th2-signaling pathway were reduced in lung tissues on treatment with the miR-396 mimics.

Conclusions
Our data suggest that miR-396 acts in a negative feedback loop to control the production of IL-5/IL-13 T cells and might thus impact the T-cell responses in asthma. Our results suggest for the first time that plant miR-396 from astragalus root of Chinese herbs plays a key role in regulating GATA-3 expression and could be useful in developing better therapeutic strategies for alleviating lung inflammations.