bluuebunny/crossref_metadata_2025_split huggingface dataset:
Depletion of islet resident macrophages protects mice from type 1 diabetes
Authors: Carrero Javier A. , McCarthy Derrick , Ferris Stephen , Wan Xiaoxiao , Hu Hao , Zinselmeyer Bernd , Vomund Anthony , Unanue Emil 
Published: January 2023

Abstract
Tissue resident macrophages are found at birth in the islets of Langerhans of all strains of mice examined. To examine the macrophage’s role in islet homeostasis and diabetogenesis, we depleted the cells using a monoclonal antibody against the CSF-1 receptor. Depletion of islet macrophages in the C57BL/6 mouse strain for 2–6 weeks did not affect multiple parameters of homeostasis including glucose tolerance, insulin content, or whole islet transcriptome. In contrast, depletion of the islet macrophages in 3 week old diabetes-prone NOD mice led to multiple changes in the progression of disease. First, there was a reduction in CD4 T cells and dendritic cells that infiltrate islets at 4–6 weeks of age. Second, there was a reduction in the presentation of insulin-derived peptides to T cells by dispersed islet cells. Third, the development of autoimmune diabetes was significantly reduced. The protection from diabetes induced by anti-CSF-1 receptor antibody was effective even when treatment was started at 10 weeks of age, a time where NOD mice have significant infiltration in their islets. Despite the protection from diabetes, mice treated with anti-CSF-1 receptor antibody at both 3 and 10 weeks of age harbored extensive leukocytic infiltration into islets when examined at 20–40 weeks of age. Treatment with an anti-PD-1 antibody led to immediate diabetes progression in all of the long-term protected NOD mice. These results show that depletion of islet-resident macrophages limited the islet leukocytic infiltration in the early phase of diabetogenesis and also permitted the establishment of a long-lived protective regulatory milieu late in the disease.
Transcriptomic meta-analysis reveals signatures of chronic inflammation in the classical monocyte population
Authors: Golden Jackelyn , Richardson Brian , Seth Divya , Cartwright Michael , Sekaly Rafick-Pierre , McCormick Thomas S. , Cooper Kevin D. , Cameron Cheryl M. , Cameron Mark J. 
Published: January 2023

Abstract
Individuals with chronic diseases are reported to have increased classical monocytes (CD14++CD16neg) which can be activated by an infectious agent and/or inflammatory milieu. Both psoriasis and HIV are considered chronic inflammatory diseases and affected individuals display alterations in monocyte phenotype and function. Moreover, individuals with either psoriasis or HIV demonstrate a significantly increased risk of developing cardiovascular disease (CVD). We sorted classical monocytes from psoriatic and healthy controls and compared them to classical monocytes from PLHIV individuals (elite controllers (EC) and non-controllers (NC, cART suppressed). Using RNA-Seq, we identified significant differentially expressed genes (DEG, p&lt;0.05) in psoriasis monocytes (164 DEGs; compared to controls) and in HIV+ classical monocytes from ECs (540 DEGs; compared to NC). We then performed a meta-analysis of the psoriasis transcriptome to the EC-HIV+ transcriptome, revealing a common set of DEGs comprising a unique gene signature involving cellular stress, chemokines, adhesion, and the clotting cascade. We further analyzed the common DEGs via pathway analysis (p & false discovery rate&lt;0.05) and STRING analysis to reveal a common dysregulated network of DEG between psoriasis and HIV. Importantly, we identified a focused network of DEG that may hallmark chronic inflammation in monocyte phenotypes. Therefore, our transcriptional meta-analysis identified candidate biomarkers that may underlie common pathologic mechanisms in psoriasis and HIV and serve as highly refined targets to treat not only primary disease, but also associated comorbidities (e.g. CVD) related to inflammation.
Intravenous anesthetic propofol and its analogue flopofol attenuated 5-lipoxygenase function and leukotriene B4 production
Authors: Yuki Koichi , Koutsogiannaki Sophia 
Published: January 2023

Abstract
Anesthesia is a routine clinical practice in surgical and interventional procedures, provided by using volatile and intravenous anesthetics. A growing literature suggests that anesthetics affect immune cellular function, and it is of great importance to understand the mechanism given an increased number of immunocompromized patients undergo anesthesia in current practice. Propofol is a very common intravenous anesthetic. We found that propofol attenuated the production of leukotriene B4 (LTB4), a major neutrophil chemoattractant, in addition to other leukotrienes in our experimental sepsis model. Because leukotrienes are produced via 5-lipoxgenase (5-LOX) activity, we hypothesized that propofol would attenuate 5-LOX activity. Our in vitro experiments using N-formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated neutrophils and 5-LOX transfected HEK cells showed that propofol attenuated 5-LOX activity. Using photoactivable propofol called azi-Pm, we showed that propofol directly bound to 5-LOX at functionally active sites. Flopofol is a propofol analogue with the substitution of 1-hydroxyl group to fluorine, and previously shown to lack anesthetic effect. In contrast, this analogue also attenuated 5-LOX activity and reduced LTB4 production, suggesting the possibility to use anesthetic as a prototype of immunomodulator. In addition, the impact of propofol in neutrophil function needs to be delineated in clinical scenario.
Influenza A virus infection causes chronic lung disease linked to IL-13 and mucin expression at sites of viral remnants
Authors: Keeler Shamus P. , Agapov Eugene , Hinojosa Michael E. , Letvin Adam N. , Wu Kangyun , Holtzman Michael J. 
Published: January 2023

Abstract
Clinical and experimental observations suggest that the development of chronic obstructive lung disease is linked to respiratory viral infection. However, there is no experimental model that establishes the long-term aspect of this relationship using a human pathogen with high level viral replication. Here we show that influenza A virus (IAV) infection achieves million-fold increases in viral load in the lung and dose-dependent severity of acute illness followed by long-term persistence of negative and positive strand viral remnants and similarly dose-dependent development of chronic lung disease. The disease persists for at least 6 months and is manifested by focal areas of bronchiolization and mucus production that contain increased levels of IAV remnants along with mucin Muc5ac and Il13 mRNA expression. These disease manifestations and airway hyper-reactivity are attenuated with loss of IL-13 production or signaling (using Il13 or Stat6 deficient mice). These deficiencies also cause reciprocal increases in l17a mRNA and neutrophils in the lung, however, post-viral mucus production and hyper-reactivity are unchanged with combined IL-13–IL-17a deficiency compared to IL-13 deficiency or with STAT6-IL-17a deficiency compared to STAT6 deficiency. The results establish the capacity of a potent human respiratory virus to produce chronic lung disease at sites of viral remnants, presumably reflecting locations of viral replication that eventually translate to IL-13-driven mucus production. Since highly infectious mouse parainfluenza virus causes similar disease, the findings also implicate high-level viral replication and severity of infection as key determinants of hyper-secretory lung diseases such as asthma and COPD.
MARCH1 plays an indispensable role in the development of airway allergic immunity and asthma
Authors: Castellanos Carlos A. , Ren Xin , Huang Xiaozhu , Shin Jeoung-Sook 
Published: January 2023

Abstract
Membrane associated RING-CH-1 (MARCH1) is an E3 ubiquitin ligase expressed mostly by antigen presenting cells (APCs) of the hematopoietic lineage. MARCH1 ubiquitinates surface MHCII and CD86 targeting these molecules for lysosomal degradation. MARCH1-mediated MHCII ubiquitination is crucial for thymic regulatory T cell generation. Whether MARCH1 plays a role in airway allergic inflammation remains unknown. We interrogated the function of MARCH1 in a well-established house dust mite (HDM) driven allergic inflammation mouse model of asthma. Despite displaying higher levels of MHCII and CD86 in APCs, MARCH1-deficient mice were incapable of developing allergic airway inflammation comprising of lung eosinophil accumulation, Th2 cell production of IL-4 and IL-13 cytokines, serum IgE responses, airway hyper-reactivity and mucus production. MARCH1-deficient mice failed to elicit IL-4 production from naïve CD4+ T cells in the lung draining lymph node during HDM sensitization. In addition, MARCH1-deficient mice did not effectively expand effector Th2 cells in the lungs after HDM challenge. Importantly, ablation of MARCH1 expression protected HDM sensitized mice from developing airway inflammation and hyper-production of IgE following re-exposure to HDM. These findings indicate that MARCH1 plays a crucial role in the initiation and progression of allergic airway inflammation, raising the possibility that modulating MARCH1 function might be therapeutically beneficial in asthma treatment.
A novel role of human lung endothelial cells in allergic airway disease by producing and responding to IL-33
Authors: Howard Chanie L. , Decker Donna C. , Swanson Ivy Aneas , Blaine Kelly M. , Nobrega Marcelo A. , Sperling Anne I. 
Published: January 2023

Abstract
Allergic asthma affects more than 300 million people worldwide and is characterized by airway hypersensitivity and eosinophilia. A prevalent feature of allergic asthma is increased serum IL-33 levels, and asthma GWAS have demonstrated that SNPs in the IL-33 locus are significantly associated with disease. While IL-33 and its downstream type 2 responses have been extensively studied in murine models of asthma, much less is known about the regulation of human IL33. Analysis of the mouse and human IL33 loci reveals little genomic conservation between the two species in non-coding regions. We generated a novel BAC transgenic mouse strain containing the human IL-33 locus with a fluorescent reporter to interrogate the regulation and expression of human IL-33. Surprisingly, the mice expressed human IL-33 primarily in endothelial cells, whereas murine IL-33 was expressed primarily in epithelial cells. These results mirror the expression profiles of IL-33 in primary human lung cells from the LungGENS database, thus demonstrating that our novel mouse model faithfully replicates human IL-33 expression. To understand how human IL-33 in the lung is regulated and expressed during inflammation, we examined BAC transgenic mice challenged with either house dust mite extract (HDM) or poly(I:C). In contrast to murine IL-33, expression of human IL-33 was reduced during allergic inflammation. We tested whether IL-33 is able to autoregulate itself via a negative feedback loop. Indeed, IL-33 administration downregulated the expression of human IL-33 in lung endothelial cells. Together, these data emphasize a distinct and novel role in humans for lung endothelial cells in allergic airway disease by producing and responding to IL-33.
Estrogen contributes to sex differences in M2-polarization during asthma
Authors: Keselman Aleksander M. , Fang Jessie , White Preston B. , Heller Nicola M. 
Published: January 2023

Abstract
Asthma is a chronic inflammation of the airways that exhibits sex differences, affecting mostly boys in childhood and women in adulthood. Alveolar macrophages have emerged as major mediators of allergic lung inflammation. We hypothesized that alveolar macrophages respond to estrogen by enhancing M2 responses and thereby contribute to sex differences in asthma. We found that macrophages from female mice exhibited increased expression of canonical M2 markers like Ym1 and Arg1 in response to IL-4. Signaling through ERα further enhanced IL-4-induced M2 gene expression in macrophages from female mice. The promoters of these genes contained increased abundance of transcriptionally active modifications like H3Ac and H3K4Me3 in macrophages from female mice. Using an OVA model of allergic lung inflammation, we found that female mice exhibited enhanced M2-polarization in vivo after allergen challenge. M2-polarization was impaired in ovariectomized (OVx) mice and but was restored with estrogen replacement. Further, we established a mixed bone marrow chimera model whereby irradiated mice were reconstituted with a 1:1 mix of bone marrow from CD45.1+ WT and CD45.2+ LysMCREERαflox/flox mice. In these mice, ERα-sufficient alveolar macrophages exhibited enhanced M2-polarization compared to ERα−/− alveolar macrophages. ERα−/−cells were largely retained in the bone marrow, suggesting that E2 regulates leukocyte trafficking during lung inflammation. Together these data suggest that sex and hormonal factors contribute to sex differences in macrophage responses during asthma. Understanding the role of estrogen signaling in M2-polarization is paramount for identifying novel therapeutic targets to better treat women with asthma.
The loss of DGK protects against allergic airway inflammation and airway hyperresponsiveness
Authors: Singh Brenal , Lu Wen , Schmidt-Paustian Amanda , Kambayashi Taku 
Published: January 2023

Abstract
Asthma is a chronic allergic inflammatory airway disease that is caused by aberrant immune responses to inhaled allergens, which leads to airflow obstruction driven in part by increased sensitivity of airway smooth muscle to contractile agonists, a process known as airway hyperresponsiveness (AHR). The inflammation of allergic asthma is driven by type 2 cytokines released by Th2 CD4+ T cells and group 2 innate lymphoid cells (ILC2) in the lung. Here, we report that targeting DAG kinase zeta (DGKζ), a negative regulator of DAG-mediated cell signaling, protects against allergic asthma. DGKζ knockout (KO) mice exhibited reduced type 2 airway inflammation and were completely resistant to AHR induction in a mouse model of allergic asthma. Surprisingly, the mechanism by which DGKζ protected against airway inflammation and AHR were separable. Targeted deletion of DGKζ in T cells led to decreased type 2 inflammation with no attenuation of AHR. In contrast, conditional deletion of DGKζ in airway smooth muscle cells led to decreased AHR despite no changes in airway inflammation. Importantly, the pharmacological inhibition of DGK provided protection against airway inflammation and AHR in mice, and also reduced bronchoconstriction of human airways. Together, our data suggest that DGKζ is potentially a novel therapeutic target for allergic asthma. Moreover, the targeted deletion of DGKζ reveals that the inflammatory and AHR components of allergic asthma are not as interdependent, as generally believed.
TRIM37 regulates allergic airway inflammation in a murine model of asthma
Authors: Chang Hung-Chih , Lu Jean , Chen Hui-Chen 
Published: January 2023

Abstract
Patients with asthma, an allergic airway inflammation disease caused by dysregulation of T helper cell type 2 (TH2), have dramatically increased in the past decades and cost of care is more than 11.3 billion per year. Evidence reveal that activation of pattern recognition receptor (PRR) signaling in both hematopoietic and non-hematopoietic compartment are critical for the development of allergic airway inflammation. TRIM37 is the only member of Tripartite motif (TRIM) family protein that contains TRAF domain, studies indicated that TRIM37 might involve in regulating PRR-, TNFR- and cytokine-mediated signaling pathways suggesting its important role in regulating immune responses. However, whether there is functional impact of TRIM37 on the development of asthma remains to be examined. Using immunohistochemistry staining of lung tissues from naïve and allergen-induced inflamed mice, positive staining of TRIM37 was observed in airway epithelial cells. Interestingly, the expression level was further augmented when lung was inflamed. Functional analysis of TRIM37 indicated that TRIM37 was involved in regulating TLR-mediated signaling in airway epithelial cells, as production of pro-inflammatory cytokines was reduced in response to TLR agonists when TRIM37 was knocked-down in the cells. Furthermore, when TRIM37 were knocked-down by intratracheally delivering lentivirus carrying TRIM37shRNA into the sensitized mice before challenge showed that knockdown of TRIM37 expression in the lung during challenge diminished cardinal features of asthma. These findings suggested the involvement of TRIM37 in allergic airway inflammation.
Soluble LOX-1: A Potential biomarker for SLE and Cardiovascular Comorbidity
Authors: Sagar Divya , Gaddipati Ranjitha , Ongstad Emily , Rahman Saifur , Belkhodja Mehdi , Bhagroo Nicholas , An Ling-Ling , Hasni Sarfaraz , Siegal Richard , Sanjuan Miguel A. , Kolbeck Roland , Karathanasis Sotirios , Sims Gary P. , Gupta Ruchi 
Published: January 2023

Abstract
Cardiovascular disease is the leading cause of mortality among systemic lupus erythematosus (SLE) patients. LOX-1 is a scavenger receptor strongly implicated in plaque formation, progression and destabilization. It gets upregulated during vascular inflammation on endothelial cells, monocytes, macrophages, smooth muscle cells and platelets. Soluble LOX-1 (sLOX-1) can serve as a potential biomarker for identifying SLE patients with increased cardiovascular risk. In a 120 SLE patient cohort, circulating sLOX-1 levels were 2-fold higher compared to healthy controls, particularly in those14–40 years of age. Patients with high sLOX-1 had elevated proinflammatory HDL, oxLDL, CRP and SAA levels; known markers for vascular injury. High sLOX-1 patient HDL had higher cholesterol content and lower efflux capacity compared to healthy and low sLOX-1 HDL. Both patient derived monocytes and low-density granulocytes (LDGs) express significant levels of membrane LOX-1 compared to controls. Monocytes when conditioned with oxLDL and stimulated with immune complexes, release significant levels of sLOX-1 and cytokines through the LOX-1 receptor. SLE HDL failed to nuclear colocalize the inflammation resolution factor ATF3, in monocyte derived macrophages. Additionally, patient LDGs underwent rapid NETosis in the presence of immune complexes when primed with oxLDL, through the LOX-1 receptor. Disease modified lipoproteins in SLE function as LOX-1 ligand contributing to inflammatory immune activation adding to cardiovascular risk. Hence, sLOX-1 can be predictive of increased cardiovascular risk and LOX-1 receptor blockade may be a promising target for ameliorating cardiovascular damage in SLE.
Lupus nephritis: the roles of C1q and C3 in preventing antibody mediated injury
Authors: Skopelja-Gardner Sladjana , Peng YuFeng , Colonna Lucrezia , Sun Xizhang , Tanaka Lena , Salant David , Elkon Keith B. 
Published: January 2023

Abstract
Lupus nephritis (LN) is a common and serious complication of systemic lupus erythematosus (SLE). While defective clearance of apoptotic cells (AC) and immune complexes (IC) is implicated in LN pathogenesis, the precise way in which different complement components impact kidney protection and injury is unknown. To address this, we created C57BL/6 mice with defective clearance of AC (Mfge8 deficiency) and anti-chromatin antibodies (sle1 interval) that were also deficient in either C1q [C1q Triple mutant (C1qTM)] or C3 (C3TM). Both C1q and C3 TM mice spontaneously developed anti-DNA antibodies and glomerulonephritis associated with glomerular IgG deposits after the age of 6 months. To dissociate the effects of complement on B cells versus effects on the kidney, we examined the effects of antibody mediated kidney injury (nephrotoxic nephritis, NTN) in mice deficient in the clearance of AC with complement deficiency [double knockout (DKO) (Mfge8 C1q or Mfge8 C3) mice]. In NTN, 50% of C1q DKO and 25% of C3 DKO, but no Mfge8 KO, died after NTN induction and the surviving C1q DKO mice developed severe proteinuria. Surprisingly, both spontaneous and NTN-induced nephritis in C1q TM or C1q DKO had strong glomerular C3 and C3d staining, while strong staining for the membrane attack complex (MAC) was observed in C3 TM or C3 DKO mice. These findings indicate that: 1) C1q and C3 independently protect against kidney injury separate from their effects on B cell function 2) In the presence of excess AC and low C1q, antibody mediated kidney injury is associated with C3 activation, presumably by the lectin or alternative pathway and 3) In the presence of excess AC and low C3, antibodies can cause MAC activation by pathways that remain to be determined.
Increased NKp44 (−) ILC3s in the peripheral blood of patients with Crohn’s disease
Authors: Li Jian , Drourr Joshua , Glover Sarah 
Published: January 2023

Abstract
Crohn’s disease (CD) is a complex chronic immune-mediated disorder of the human gastrointestinal tract. Emerging evidence indicates an essential role of the innate immunity in this process. Newly identified innate lymphoid cells (ILCs) are important components of the innate immunity. They act as the first line of defense to eliminate the invading pathogens. Previously, we have reported that IFN-γ-producing CD127 (+) ILC1 subset accumulated in the inflamed terminal ileum of CD patients at the expense of IL-22-producing NKp44 (+) ILC3s. This ILC phenotypic alteration was associated with the expansion of pathogenic Th17/Th1 subset among the diseased tissues. In order to further understand the contribution of ILCs to the pathogenesis of CD, we evaluated the aberrant ILCs’ responses in the peripheral blood of active CD patients in this study. We noticed that the frequency of IFN-γ-producing-CD127 (+) ILC1s was increased in the circulation of CD patients compared to donors. Furthermore, the frequency of NKp44 (−) CD117 (+) ILC3s was also significantly increased. Interestingly, they did not produce any of the common ILC cytokines: IL-17A, IL-22 and IFN-γ which is consistent with their ILC progenitor status in recent reports. In addition, almost half of the NKp44 (−) CD117 (+) ILC3s in the peripheral blood of CD patients were HLA-DR (MHC-II) positive which reveals their potential to interact and regulate systemic adaptive immunity, especially CD4 T cell responses. Different from ILC1s and ILC3s, the frequency of CRTH2 (+) ILC2s was decreased. More detailed analysis of the dysregulated innate and adaptive immune responses will help us to better understand the mechanism of CD pathogenesis and develop more novel therapeutic strategies.