bluuebunny/crossref_metadata_2025_split huggingface dataset:
TLR9 activation impairs phagocytosis-induced neutrophil apoptosis and prolongs E. coli-induced acute lung injury
Authors: Filep Janos G , Edner Natalie , de Oliveira Lima Dos Santos Everton , Sekheri Meriem , El Kebir Driss 
Published: January 2023

Abstract
Neutrophil dysfunction, resulting in delayed apoptosis and inefficient bacterial clearance, is a characteristic feature of severe pathologies, including sepsis and cystic fibrosis. Human neutrophils detect and respond to bacterial DNA (CpG DNA) through TLR9. We investigated the impact of CpG DNA on phagocytosis, phagocytosis-induced neutrophil apoptosis and clearance of E coli. Culture of human neutrophils with CpG DNA (0.1–3.2 μg/ml) resulted in decreased phagocytosis of opsonized E. coli or yeast. CpG DNA upregulated C3R (CD11b) expression, downregulated C5aR (CD88) expression and induced release of neutrophil elastase. C5aR cleavage was prevented by a specific neutrophil elastase inhibitor and the broad-spectrum serine protease inhibitor PMSF. Consistently, CpG DNA reduced phagocytosis-induced NADPH oxidase-mediated activation of caspase8 and caspase-3. These actions of CpG DNA were blocked by the telomere-derived TLR9 inhibitory oligonucleotide 5′-TTT AGG GTT AGG GTT AGG G-3′. In mice, CpG DNA impaired pulmonary clearance of E coli, suppressed neutrophil apoptosis and delayed resolution of lung injury evoked by intratracheal instillation of live E. coli. Genetic deletion of TLR9 rendered mice unresponsive to CpG DNA. These results identify a novel mechanism, neutrophil elastase-mediated inactivation of C5aR-mediated phagocytosis, by which CpG DNA could contribute to neutrophil dysfunction and prolongation of tissue injury. Our findings also suggest a therapeutic potential for TLR9 antagonists or neutrophil elastase inhibitors for enhancing clearance of bacterial infections in an environment where bacterial DNA is abundantly present.
Type 2 innate lymphoid cells impede IL-33-mediated tumor suppression
Authors: Long Alan W , Dominguez Donye , Qin Lei , Chen Siqi , Fan Jie , Zhang Minghui , Zhang Bin 
Published: January 2023

Abstract
Although a number of studies have recently explored the contribution of the adaptive immunity in interleukin 33 (IL-33)-mediated antitumor effects, innate immune involvement has been poorly characterized. Utilizing Rag1−/− mice (lacking T and B lymphocytes), we show here that either systemic administration of recombinant IL-33 or ectopic expression of IL-33 in melanoma cells is sufficient to inhibit tumor growth independent of adaptive antitumor immunity. We have demonstrated that IL-33-mediated antitumor effects relate to expansion and activation of NK cells. Interestingly, IL-33 also promoted the expansion of active type 2 innate lymphoid cells (ILC2s) via its receptor, ST2, which in turn inhibited NK activation and cytotoxicity. This IL-33-induced ILC2 activity coincided with greater expression of the immunosuppressive ecto-enzyme CD73. Removal of CD73 from ILC2s in culture with NK cells resulted in markedly increased activation levels in NK cells, offering a potential mechanism by which ILC2s might suppress NK cell-mediated tumor killing. Thus, our data reveal an important contribution of IL-33-induced ILC2 to tumor growth by weakening NK cell activation and tumor killing, regardless of adaptive immunity.
The Roles of Tumor-associated Neutrophils in Colorectal Cancer Treated with Different Combinatorial Immunotherapies
Authors: Tsai I-Ting , Chang Ching-Cheng , Wu Chia-Jen , Wu Ping-Yi , Tao Mi-Hua 
Published: January 2023

Abstract
Cancer immunotherapy can elicit robust tumor-specific immune responses that can generate durable tumor regression or eradication. Immune checkpoint blockade specific to programmed death-1/ligand-1 (PD1/PDL1) have shown durable clinical responses in various cancer types but benefit only a small portion of patients. Interleukin 12 (IL-12) and granulocyte macrophage colony-stimulator factor (GM-CSF) have shown potent antitumor activities through activating innate and adaptive immunities, and reprogramming tumor-promoting myeloid cells from immune-suppressive to immune-active phenotypes. In this study, we showed the effect of radiation, which increased release of tumor antigens so that augment the efficacy of immunotherapy, in combination with IL-12/GM-CSF (RT/12GM) or anti-PDL1 antibody (RT/PDL1) on TAN in advanced 14-day-CT26 colorectoral cancer. We found that both combination treatment significantly suppressed tumor growth, only RT/12GM but not RT/PDL1 can cure mice; radiation or immunotherapy alone single therapies were much less effective. Mechanistic analysis showed that RT/12GM, but not RT/PDL1, greatly increased accumulation of TAN. These TANs were not only impaired in their suppressive activities, but also able to induce T cell proliferation, in accordance with their increased expressions of MHC class I and II, CD40 and CD86, indicating they presented in a status with higher Ag presentation ability. Antibody depletion experiments showed that TAN was required for tumor regression in RT/12GM therapy. Together, our data demonstrate that combination of radiotherapy and IL-12/GM-CSF improved antitumor immunity through enhancing Ag presentation activity and reducing immunosuppressive functions of TAN.
STAT4 is required for protective Innate Lymphoid Cell responses to gastrointestinal infection
Authors: Dulson Sarah J , Harrington Laurie E 
Published: January 2023

Abstract
Innate Lymphoid Cells (ILCs) are a newly discovered subset of cells that serve both protective and pathogenic roles in intestinal health. ILCs consist of three defined subgroups and perform effector functions similar to CD4 T cells. However, ILCs lack a specific antigen receptor and are activated directly by cytokines early during an immune response. Since the initial events in an immune response can dictate the ability of the host to control intestinal infection, it is critical to identify molecules that regulate ILC function. Signal transducer and activator of transcription 4 (STAT4) is important for driving many pro-inflammatory responses and phenotypes in T cells, but its effects on ILC development and function remain unclear. Contrary to its known role in Th1 cell biology, we find STAT4 to be dispensable in Group 1 ILC (ILC1) development. However, we observe that STAT4 is critical for IFN-γ production by ILC1s, thus influencing the capacity of this subgroup to mount an effector response. Whereas STAT4 deficiency did not impact IL-22 or IL-17 production by ILC3s, the transcription factor specifically modulates IFNγ production by a plastic Tbet+ subgroup of ILC3s that is greatly expanded in response to inflammation. Importantly, STAT4 signaling is also critical for survival against a genetically modified strain of Listeria monocytogenes that is able to model human Listeriosis in mice. Furthermore, both ILC1 and ILC3 respond to infection with robust IFNγ production, and when ILCs are depleted mice are unable to mount a protective innate response and succumb earlier to infection. These results indicate that STAT4 signaling influences critical responses by ILCs, thereby contributing to host protection against intestinal infection.
Inhibition of Innate Lymphoid Cell Activation by Interleukin-23 Secreting Dendritic Cells During Bordetella pertussis Infections in Mice
Authors: Santos Daniel Rebelo , Nguyen Alana , Stokes Jennifer , Pavlov Nicole , Abramson Tzvia 
Published: January 2023

Abstract
Bordetella pertussis (B. pertussis), the causative agent of whooping cough, is a highly contagious respiratory tract disease marked by extensive damage to the mucosal lining and a delay in immune response due to the pertussis toxin (PTX). In this study, the focus is on the characteristics and mechanisms of two innate immune cell populations, the IL-23-secreting dendritic cells (DCs) and the IL-22-secreting innate lymphoid cells (ILCs). We hypothesize that infection with B. pertussis interferes with the IL-23/IL-22 axis pathway due to PTX production. We compared these immune responses in mice models of whooping cough, triggered by B. pertussis (prolonged disease) or Bordetella parapertussis (B. parapertussis) – an acute version of the infection, lacking PTX. Flow cytometry studies show an increased in lung DCs at 2dpi with B. parapertussis compared to B. pertussis and uninfected mice. At 2dpi with B. parapertussis, more lung CD11b+ DC at secrete IL-23 compare to B. pertussis. The percentage of ILC3 is equally increased at 2dpi with B. pertussis and B. parapertussis-infected mice. Proliferation analyses suggest that residential ILCs proliferate locally rather then recruited during infection to the lungs. Despite the increase in IL-23-producing DCs, no differential expression of IL-22 by ILC3 was observed between infections and uninfected mice. Further studies would verify the nature of this inhibition and whether it is translated to a reduced level of antimicrobial substances secreted by lung epithelial cells. The outcomes of this study may clarify the inability of these innate immune responses to resolve B. pertussis infection early.
Protection from Staphylococcus aureus sepsis by bacterial exopolysaccharide
Authors: Paik Wonbeom , Paynich Mallory L , Alonzo Francis , Knight Katherine L 
Published: January 2023

Abstract
Sepsis is the most severe presentation of systemic infection with up to 50% mortality rates. The leading etiological agent of sepsis is a Gram-positive bacterium, Staphylococcus aureus. Antibiotics are the only effective therapy for S. aureus sepsis, and widespread resistance to multiple antibiotics is a major concern. Novel therapeutic agents for sepsis are critically needed. We previously showed that exopolysaccharides (EPS) derived from a probiotic bacterium, Bacillus subtilis, protects hosts from inflammatory disease by the induction of anti-inflammatory M2 macrophages. Using a murine systemic infection model, we tested if EPS also has therapeutic potential for S. aureus sepsis. We treated mice with EPS prior to infection with S. aureus and found that weight loss, serum proinflammatory cytokine levels, and bacterial burden in the liver were mitigated compared to vehicle-treated controls. We also found that compared to cells from vehicle-treated mice, peritoneal cells from EPS-treated mice suppress growth of serum-opsonized S. aureus in vitro. We purified peritoneal F4/80-positive macrophages from EPS-treated mice and found that they were responsible for suppressing S. aureus growth by peritoneal cells. We confirmed this by depletion of macrophages from mice using clodronate-loaded liposomes, which mitigated suppression of S. aureus growth by peritoneal cells from EPS-treated mice. We suggest that B. subtilis-derived EPS may be useful for prevention and/or treatment of S. aureus sepsis.
IL-33 signaling regulates innate IL-22 production via suppression of PGE2 during lung fungal infection
Authors: Garth Jaleesa M , Reeder Kristen M , Mackel Joseph , Dunaway Chad , Blackburn Jonathan , Steele Chad 
Published: January 2023

Abstract
Members of the IL-1 family play both protective and regulatory roles in immune defense against the opportunistic mold Aspergillus fumigatus. Here, we investigated the role of the IL-1 family member IL-33 in lung defense after acute A. fumigatus exposure. IL-33 was detected in nanogram amounts in the naïve lung, which further increased after exposure to A. fumigatus in a Dectin-1 independent manner. Mice deficient in the receptor for IL-33 (IL-1RL1) unexpectedly demonstrated enhanced innate lung clearance of A. fumigatus. IL-33 functioned as a negative regulator of IL-22, as IL-22 was elevated in fungal-exposed Il1rl1−/− mice and IL-33 administration to normal mice attenuated fungal-induced IL-22 production. IL-33 mediated regulation of IL-22 did not involve the modulation of IL-23 but rather prostaglandin E2 (PGE2); PGE2 was significantly increased in fungal-exposed Il1rl1−/− mice and normal mice produced less PGE2 after fungal exposure when administered IL-33, suggesting that IL-33 mediated regulation of IL-22 occurred at the level of PGE2. This was confirmed by in vivo cyclooxygenase 2 (COX-2) inhibition and specific inhibition of PGE2 in vitro, both of which attenuated fungal-induced IL-22 in Il1rl1−/− mice. This study establishes novel mechanisms of IL-22 induction via PGE2 and regulation of the PGE2-IL-22 axis via IL-33 signaling during lung fungal exposure.
Dendritic cell-intrinsic TLR signaling regulates polymicrobial sepsis
Authors: Liu Bei , Iwanowycz Stephen , Fan Hongkuan 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen-presenting cells that play a critical role in both innate and adaptive immune response. DCs recognize and respond to bacteria through multiple pattern-recognition receptors, including Toll-like receptors (TLRs). Heat shock protein gp96 is a master chaperone for TLRs in the endoplasmic reticulum and plays critical roles in innate immunity. Sepsis is a clinical syndrome caused by a severe immune response to infection. However, the role of DC-intrinsic TLRs in sepsis has not been studied. Using a unique DC-specific gp96 knockout (KO) mouse model, we observed that gp96-deficient DCs were unable to respond to both surface and intracellular TLR ligands. Our DC-specific gp96 deficient mice present a DC-specific pan TLR KO mouse model. We challenged WT and KO mice with a lethal dose of LPS, and we found that WT mice significantly produced more serum TNF-a than did KO mice. Consistent with the detrimental effect of this cytokine in sepsis, we found that the WT mice were more susceptible to LPS-induced sepsis than the KO mice. Furthermore, using a well-defined sepsis model of cecal ligation and puncture (CLP), we found that KO mice exhibited significant higher survival rates (33%) compared to littermate WT controls (5%, p&lt;0.05). Collectively, our study demonstrates that DC-specific gp96 KO mice were able to mount effective responses against polymicrobial sepsis, underscoring the importance of DC-intrinsic TLR signaling in innate immunity and sepsis outcomes.
A mouse model of age-associated tuberculosis reactivation positions KLRG1 as a modulator of disease progression.
Authors: Turner Joanne , Gautam Shalini , Dwivedi Varun 
Published: January 2023

Abstract
Tuberculosis (TB) in the elderly can arise from reactivation of M.tb infection that was acquired when younger and immune exhaustion or senescence is thought to play a role in this process. KLRG1 is an inhibitory receptor of T cell function and its expression is elevated on T cells with increasing age and T cell differentiation status. We have previously shown using KLRG1-KO mice that the absence of KLRG1 provides a survival advantage to chronic M.tb infected mice, showing proof of concept for an inhibitory role of this receptor during M.tb infection. We hypothesized that KLRG1 would have a more significant role in a model of age-associated reactivation TB where immuno-senescence can also play a role. We infected young wild type (WT) and KLRG1 KO mice with M.tb and then reduced the M.tb CFU to low levels using the modified Cornell model (2–3 months isoniazid/rifampicin in water), allowing mice to live into old age. Mice were sampled every 2–4 months for determination of TB reactivation and immune function. M.tb CFU were moderately increased in lung and spleen of WT mice around 14 months of age, an age that is associated with shifts in T cell phenotype and function. For WT mice M.tb CFU reached levels similar to a chronic M.tb infection approximately 18–20 months of age. A significant increase in total T cell numbers and antigen specific CD4 T cells in the lung also occurred at that age. In contrast, KLRG1 KO mice had a substantial delay in reactivation of M.tb, indicating that KLRG1 has a functional inhibitory role during M.tb infection. Our data suggest that modulating KLRG1 function, or the development of T cells that express KLRG1, can have beneficial outcome on the susceptibility of the elderly to succumb to reactivation TB.
The analysis of a Puerto Rican cohort of Essential Thrombocytemia patients
Authors: Maysonet-Cruz Johanna , Calzada Natalia , Washington Anthony V. , Hunter Robert 
Published: January 2023

Abstract
Essential Thrombocytemia (ET) disorder, part of the group of myeloproliferative disorders, has been related to acquired mutations that constitutively activate the JAK2 pathway, accordingly JAK2V617F is present in the 56% of ET patients. ET decreases life expectancy and its effects are detrimental on the mid-fifties population, therefore, it is important to understand and devise methods to improve its treatment. For this reason, we completed a comparative analysis of 37 different cytokines in a cohort of 23 Puerto Rican ET patients and 11 controls. Using Mann Whitney comparative analysis between the status of the JAK2V617F mutation and cytokine profiles have revealed that JAK2V617F positive patients have a significantly higher median values of IL-19 (ET: 6.48 pg/ml; control: 5.13 pg/ml, p-value: 0.0076), Il-28/IFNλ2 (ET: 3.76 pg/ml; control: 2.79 pg/ml, p-value: 0.0422) and IL-29/IFNλ1 (ET: 14.47 pg/ml; control: 10.3 pg/ml, p-value: 0.0332) when compared with healthy controls. TWEAK TNFSF12 (ET: 40.05 pg/ml; control: 47.77 pg/ml, p-value: 0.0437), however was significantly lower in this population. Also, we have found that JAK2V617F negative patients have significantly higher levels of IFN-α2 (ET: 14.82 pg/ml; control: 12.53 pg/ml p-value: 0.0096), IL-8 (ET: 6.93 pg/ml; control: 6.33 pg/ml, p-value: 0.0316), and IL-22 (ET: 7.865 pg/ml; control: 6.23 pg/ml, p-value: 0.0087) than control patients. Moreover, we have found that ET CALR mutants have significantly lower median levels of MPP-3 and that ET patients have higher TLT-1 levels than control patients. Together these findings could be used to enhance the characterization and improve prognosis and treatment of ET patients.
Cancer Immunotherapy: knowledge translation and outreach education
Authors: Sika-Paotonu Dianne , Laban Luamanuvao Winnie 
Published: January 2023

Abstract
It is recognised that Pacific peoples living in New Zealand in the Pacific are affected disproportionately by some cancers with the burden of cancer overall remaining a significant health concern. These communities stand to benefit from research that will contribute to improvements in health outcomes. Community engagement activities and knowledge translation efforts that involve research findings of relevance to Pasifika populations are of importance in supporting the dissemination of knowledge and dialogue. Limited attempts however have been made to communicate major scientific research findings to the Pasifika audience in a manner that is culturally appropriate, clear and meaningful. The purpose of this work was to host a knowledge translation event to present research of direct relevance and importance to Pasifika communities that included a major compartment dedicated to increasing clarity and awareness of emerging cancer immunotherapeutic based strategies for treating cancer. This event was well attended by members of the Pasifika community that included health leaders and representatives, families, scientists, students, academics, health researchers, community representatives and other interested parties. Verbal and written feedback highlighted the programme overall was highly evaluated by those who were in attendance. This knowledge translation and science communication event successfully facilitated engagement and open dialogue with Pasifika members of the health workforce community that included raising awareness of immunotherapeutic strategies for cancer.
Phenotypic characterization of fifty surface markers expressed by human M1 and M2a macrophages cultured with different serums and in the presence or absence of polarizing cytokines.
Authors: Bonnevier Jody L , Hammerbeck Christopher , Goetz Christine , Newman Kristal , Aggeler Birte 
Published: January 2023

Abstract
Macrophages are ubiquitously distributed throughout the various tissues of the body and perform many functions. These include inflammatory responses against pathogens by classically activated M1 macrophages and the regulation of wound healing and tissue remodeling by anti-inflammatory alternatively activated M2 macrophages. The responsibility for these pleiotropic functions lies in the expression of a myriad of surface receptors unique to a given subset. Much of what we know about the function of human macrophage subsets has been gleaned by studying in vitro generated macrophages, matured in the presence of GM-CSF or M-CSF, and polarized with different cytokines. Oftentimes, culture conditions (such as the type of serum used, the duration of the culture and the use of polarizing cytokines) vary between studies making direct comparisons difficult. Furthermore, overlap in surface marker expression can make it difficult to distinguish between the different macrophage subsets.
We directly compared the expression of fifty different surface markers on M1 and M2a macrophages cultured in the presence of fetal bovine serum, human AB serum or serum free media and found that the type or presence of serum used affected the expression of several markers such as CD200R1 and CD32. Moreover, we compared the expression of these surface markers on polarized and unpolarized macrophages and determined that polarization was critical to the expression of several of these markers, such as CD38 and SLAM F7. The results of these studies should significantly expand our knowledge of the phenotypic differences between human M1 and M2a macrophages as well as demonstrate the importance of culture conditions in generating these phenotypes.
Cancer Mutations Targeting TNFRSF14 alter Microenvironment Checkpoint Interactions to Limit Tumor Clearance by Cytotoxic Cells
Authors: Sedy John R , Balmert Mary Olivia , Nguyen Jennifer , Ware Brian C , Bjordahl Ryan , Norris Paula S , Miller Brian R , Aivazian Dikran , Ware Carl F 
Published: January 2023

Abstract
The roles of many non-oncogenic mutations in cancer may influence tumor growth, survival, or how tumors interact with their surroundings. Here we characterize the functional relevance of missense mutations within the gene encoding the tumor necrosis receptor family member HVEM (TNFRSF14), a locus frequently targeted within human lymphoma and other cancers. We find that point mutations identified in human lymphoma were localized to the extracellular domain and specifically target ligand binding, resulting in preferential loss of CD160 and BTLA interactions compared to LIGHT (TNFSF14). Missense mutations were associated with alterations in cytotoxic effector cell signatures within tumor biopsies, while deletion mutations were associated with changes in myeloid cell signatures. Finally, we find that mutated HVEM proteins retained the capacity to inhibit T cell signaling through BTLA, while reducing costimulation of cytolysis in NK cells through CD160. Together, these data provide evidence for how immune selective pressures may drive mutation of TNFRSF14 resulting in greater tumor fitness.