bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of ROS on neutrophil containment of the intracellular bacteria, Listeria monocytogenes
Authors: Okunnu Busola , Berg Rance E. 
Published: January 2023

Abstract
Extracellular superoxide dismutase (ecSOD) is commonly regarded as having a protective function during ROS induced inflammation. However, using ecSOD congenic mice expressing differing levels of ecSOD activity (HI, WT & KO), we found that high ecSOD activity is not conducive to host survival during Listeria monocytogenes (Lm) infection. Interestingly, although the infected ecSOD HI mice had a higher percentage of neutrophils present in the target organs in comparison to the ecSOD KO mice, they also had a higher bacterial burden. To better understand the function of neutrophils during infection with Lm, we studied phagosomal containment in the context of varying levels of ecSOD activity. A higher percentage of KO neutrophils took up and allowed for phagosomal escape of Lm. However, although there was no difference in the relative amount of Lm that escaped per neutrophil in the context of ecSOD activity, the KO neutrophils took up more Lm than the HI neutrophils. Therefore, neutrophils from the KO mice were more effective at keeping Lm contained in comparison to the HI neutrophils. The effect of ecSOD on the ability of monocytes to contain Lm was also analyzed. It was observed that ecSOD had no effect on monocyte association and phagosomal containment of Lm. However, independent of ecSOD, a lower percentage of monocytes associate with and allow for phagosomal escape of Lm, in comparison to neutrophils. In conclusion neutrophils are more effective than monocytes at phagocytosis of Lm and ecSOD activity hinders neutrophil phagosomal containment of Lm. Future studies focused on how ecSOD activity modulates downstream neutrophil functions, such as Lm killing, will lead to a better understanding of the overall effects of ROS on neutrophil functions.
Trogocytosis: a novel mechanism neutrophils use to kill a large, motile extracellular parasite
Authors: Mercer Frances , Ng Shek Hang , Brown Taylor M. , Boatman Grace , Johnson Patricia J. 
Published: January 2023

Abstract
Trichomonas vaginalis (Tv), a human-infective parasite, causes the most common non-viral sexually transmitted infection worldwide and contributes to adverse inflammatory disorders. The immune response to Tv is poorly understood. Neutrophils (PMN) are the major immune cell present at the Tv-host interface and are thought to clear Tv. However, the mechanism of PMN clearance of Tv has not been characterized. We demonstrate that human PMN rapidly kill Tv in a dose dependent, contact-dependent and NET-independent manner. In contrast to phagocytosis, we observed that PMN killing of Tv involves taking “bites” of Tv prior to parasite death, using trogocytosis to achieve pathogen killing. Both trogocytosis and parasite killing are dependent on the presence of PMN serine proteases and human serum factors, consistent with a model that opsonins mediate initial tight contact, but that serine protease activity is required for “nibbling.” Trogocytosis has previously been described as a way for immune cells to exchange membrane proteins, as a mechanism to spread intracellular bacteria from one cell to another and for E. histolytica to injure or kill host cells. Our analyses are the first to demonstrate the use of trogocytosis by a mammalian phagocyte for pathogen clearance and reveal a novel mechanism used by PMN to kill a large, highly motile target.
Food allergy is associated with altered epithelial gene expression driven by early life dysbiosis
Authors: Plunkett Catherine H. , Feehley Taylor J. , Bao Riyue , Belda-Ferre Pedro , Hong Sung Min Choi , Campbell Evelyn , Aitoro Rosita , Nocerino Rita , Paparo Lorella , Antonopoulos Dionysios A. , Andrade Jorge , Canani Roberto Berni , Nagler Cathryn 
Published: January 2023

Abstract
A marked increase in disease prevalence has made food allergies a major public health concern. One hypothesis for this rise is that recent lifestyle factors have altered the composition of the intestinal microbiota, increasing susceptibility to allergic disease. Host-microbiota interactions are essential for immune homeostasis, and perturbations of naturally-selected bacterial populations, a condition called dysbiosis, are linked to many different pathologies. To investigate the role of the microbiota in regulating food allergies, we colonized germ free mice with bacteria from healthy or cow’s milk allergic (CMA) infants. We found that colonization with bacteria from healthy infants is sufficient to protect against sensitization to the milk allergen β-lactoglobulin (BLG). In contrast, colonization with bacteria from CMA infants fails to protect, resulting in high concentrations of BLG-specific IgE and anaphylactic responses following BLG challenge. Analysis of bacterial taxa in feces from multiple healthy and CMA infants identified significant differences in bacterial composition that distinguished health status in both the human donors and the colonized mice, emphasizing the clinical relevance of our gnotobiotic model. RNAseq of ileal epithelial cells revealed differentially expressed genes (DEGs) that separate healthy- and CMA-colonized mice. Integration of ileal bacteria and ileal DEGs identified taxa that were significantly correlated with gene expression changes. Together, these results demonstrate that the composition of the intestinal microbiota regulates systemic responses to dietary antigen and suggest that modulation of these communities may be useful in treatment or prevention of food allergy.
Engineered immunomodulatory protein tyrosine phosphatase ameliorates inflammatory skin diseases
Authors: Kim Won-Ju , Koo Ja-Hyun , Cho Hyun-Jung , Lee Jae-Ung , Kim Ji Yun , Lee Sohee , Lee Hong-Gyun , Kim Jong Hoon , Oh Mi Seon , Suh Minah , Shin Eui-Cheol , Ko Joo Yeon , Sohn Myung Hyun , Choi Je-Min 
Published: January 2023

Abstract
Atopic dermatitis and psoriasis are the two most common chronic inflammatory skin diseases with unmet needs. There are still no effective and safe topical therapeutics for inflammatory skin diseases and current developing biologics have limitation of administration methods. Here, we identified a novel transdermal delivery peptide (AP) and generated engineered immunomodulatory protein to inhibit dermatitis. AP-conjugated proteins exhibited significant intracellular transduction efficacy in keratinocytes, fibroblasts, and immune cells. Transdermal delivery of AP-dTomato protein showed localization into the dermis and epidermis in both mouse and human skin. Next, we generated AP-conjugated phosphatase domain of TC-PTP protein (AP-rPTP) for regulating cytokine and T cell receptor signaling. AP-rPTP inhibited pSTAT1, pSTAT3, pSTAT5 and pSTAT6 upon cytokine stimulation in mouse splenocytes. AP-rPTP also regulated T cell activation, proliferation and Th1, Th2 differentiation upon CD3/28 stimulation. The transdermal paper-patch of the AP-rPTP protein significantly ameliorated ear thickness, tissue inflammation, and cytokine expression in allergic dermatitis as well as in psoriasis-like mice models. These results collectively demonstrate the feasibility of utilizing AP peptide for biologic drug delivery via paper-patch and suggest AP-rPTP as a novel immune modulatory drug candidate for inflammatory skin diseases.
Molecular selection and initial characterization of a new inducer and a new destabilizer of non-bilayer phospholipid arrangements
Authors: Barbosa Sandra Sánchez , Landa-Saldívar Carla , Nevarez-Lechuga Irene , Wong Carlos , Wong-Baeza Carlos , Baeza Isabel 
Published: January 2023

Abstract
The mouse model of a lupus-like disease developed by our research group is unique, because it’s obtained by the stabilization of lipidic structures called non-bilayer phospholipid arrangements (NPAs), which induce the production of anti-NPA antibodies that trigger the disease in mice, which are in turn detected in patients with systemic lupus erythematosus. NPAs are produced when a lipid bilayer composed of conic and cylindric phospholipids, is modified by certain drugs (procainamide, chlorpromazine) or the manganese cation. Usually, drugs/substances are chosen to be tested as NPA inducers when they are known to trigger a lupus-like disease in humans. However, here we selected a group of molecules only by their structural similarity with the known inducers and the known destabilizer (chloroquine) and experimentally tested their effect on the formation or destabilization of NPAs in liposomes by flow cytometry. Firstly, we identified promethazine and procaine, similar to chlorpromazine and chloroquine, respectively. Promethazine acted as an inducer, with a broader range of concentrations of action in comparison with chlorpromazine, but it was more sensitive to the destabilizer. Procaine was found to be a weaker destabilizer than chloroquine, as it has an effect only at higher concentrations. This strategy showed that molecular characteristics could also be good predictors of their action on lipid bilayers and NPAs formation.
Soluble interleukin-27 receptor alpha is a valuable predictive biomarker for acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Authors: Ma Shoubao , Liu Shuangzhu , Gong Huanle , Wu Depei 
Published: January 2023

Abstract
Interleukin-27 receptor alpha (IL-27Rα) is a co-receptor of IL-27, which is an inflammatory cytokine and displays extensive immunological functions. It has been reported that IL-27Rα can exist in its soluble form (sIL-27Rα) in human serum and function as a natural IL-27 antagonist. In this study, we examined the serum sIL-27Rα levels and evaluated its predictive and prognosis value in aGVHD. Serum sIL-27Rα levels at the time of neutrophil engraftment were significantly decreased in grade II–IV aGVHD patients (P&lt;0.001) as well as in patients with skin (P&lt;0.01) or liver aGVHD (P&lt;0.05). sIL-27Rα at neutrophil engraftment could be used to predict grade II–IV aGVHD (AUC=0.735, 95% CI 0.618–0.853, P=0.001). Cumulative incidences of grade II–IV aGVHD (P=0.004), recurrence rate (P=0.008), and non-recurrent mortality (P=0.008) in patients with high serum sIL-27Rα (≥59.40 ng/ml) were significantly lower than those in patients with low serum sIL-27Rα (&lt;59.40 ng/ml). Multivariate analysis confirmed that low sIL-27Rα level at neutrophil engraftment (HR=2.83 95%CI 1.29–6.19, P&lt;0.01) was an independent risk factor for predicting grade II–IV aGVHD. In addition, serum sIL-27Rα were positively associated with IL-27 (R=0.27, P=0.029), IL-10 (R=0.37, P=0.0015) and HGF (R=0.27, P=0.0208), whereas negatively associated with TNFR1 (R=−0.365, P=0.0022), Elafin (R=−0.29, P=0.0117), and REG3α (R=−0.417, P=0.0003). Taken together, our findings demonstrated that serum sIL-27Rα was upregulated after allo-HSCT, their levels at neutrophil engraftment maybe a valuable predictive biomarker in predicting the incidence of moderate-to-severe aGVHD after allo-HSCT.
BMT procedure alters the functions of dendritic cells and subsequently causes pathogenic Th responses to gammaherpesvirus infection
Authors: Zhou Xiaofeng , Chadwick Matthew M. , CHan Paul R. , Wilke Carol A. , Podsiad Amy B. , Yanik Gregory A. , Moore Bethany B. 
Published: January 2023

Abstract
Hematopoietic stem cell transplantation is a standard of care for many patients with genetic disorders, autoimmune diseases and malignancies. However, stem cell recipients are often more susceptible to microbial infections even after full hematopoietic reconstitution. We have previously demonstrated that syngeneic bone marrow transplantation (syn-BMT) in mice causes increased Th17 response and decreased Th1 response to murine gamma herpesvirus MHV-68 infection leading to pulmonary fibrosis. In this study, we found that Notch2-dependent conventional dendritic cells (DCs), i.e., a set of CD11b+ DCs, are required for the Th17 response to MHV-68 infection in BMT mice, while Batf3-dependent CD103+ DCs suppress the Th17 response. Furthermore, CD11b+ DCs in BMT lungs are hyper-activated with high expression of CD80 and CD86. When co-cultured with CD4+ T cells, DCs from BMT lungs promote higher productions of both IL-17A and IFN-γ than DCs from non-BMT mice, and addition of antibodies against CD80 and CD86 abolish the productions of both IL-17 and IFN-γ. Although the DCs in the BMT lungs are potent in inducing both Th1 and Th17 responses ex vivo, they are impaired in migrating into the lung draining lymph nodes (dLNs). Surprisingly, migration of DCs into the dLNs is not required for Th17 priming, since transplanting CCR7−/− bone marrow, which gives rise to non-migrating DCs in the recipient mice, does not prevent the Th17 response, but does abolish the Th1 response, suggesting a role for peripheral priming of the Th17 response in the lung post-BMT. In summary, syn-BMT causes a hyper-activated phenotype of CD11b+ DCs that promotes a pathogenic Th17 response and also causes dysfunction in DC trafficking that is required for a maximum Th1 response.
The enigmatic impact of donor T cell subsets on the therapeutic efficacy of tolerogenic protocols for transplant rejection
Authors: Lozano Marcos Iglesias , Chicco Maria , Lee W.P. Andrew , Brandacher Gerald , Raimondi Giorgio 
Published: January 2023

Abstract
Costimulation blockade (CoB) regimens are a promising immunomodulatory strategy to prevent transplant rejection. However, we are learning that their efficacy is affected by multiple factors. Recent reports have started highlighting the unexpected capacity of passenger donor lymphocytes to enhance the recipient’s anti-graft response. New studies are necessary to understand this novel phenomenon and how it can affect the induction of transplant tolerance.
In this study we assessed if T lymphocytes contained in the donor specific transfusion (DST) inoculum, used in combination with anti-CD154 (MR1) as CoB regimen, impact the regulation of mouse skin transplant rejection. When T cells were depleted from the DST, transplant survival was almost doubled. T cell subset-depletion studies indicated, unexpectedly, that donor CD8 T cells were responsible for limiting the efficacy of the tolerogenic regimen. Even more surprisingly, the presence of CD4 T cells in DST induced a remarkable improvement in transplant survival, beyond that observed with full T cell depletion. Ongoing experiments are determining the correlation between donor T lymphocytes and variations in humoral and cellular anti-donor responses.
Overall, these data reveal the existence of a novel and unexpected opposing role of donor passenger lymphocytes that significantly modifies the therapeutic efficacy of DST+MR1 based regimens: a deleterious role for donor CD8, and a beneficial one for CD4 T cells. Identification of the specific mechanisms through which these divergent modulations of the anti-donor alloresponse are exerted could suggest significant changes in how we should approach immunoregulation, both experimentally as well as clinically.
Recipient conditioning contributes to IL-33-driven Th1 alloimmune responses following rapid ST2 upregulation on donor CD4+ T cells during lymphopenia-induced proliferation
Authors: Dwyer Gaelen K. , Mathews Lisa R. , Lucas Anna , Blazar Bruce R. , Turnquist Heth R. 
Published: January 2023

Abstract
IL-33 is augmented in recipient tissues by conditioning before allogeneic stem cell transplantation (alloSCT) and is a required signal to donor T cell for GVHD. Targetable mechanisms by which IL-33 supports GVHD are yet undefined. Conditioning causes lymphopenia-induced proliferation (LIP) and releases microbial products. These products promote myeloid cell secretion of IL-12, which induces the IL-33 receptor, ST2, on T cells in vitro. We hypothesized that IL-12 induces ST2 on donor T cells during LIP promoting IL-33 augmentation of the Th1 responses leading to GVHD. To establish the role of IL-12 in T cell ST2 expression and IL-33-mediated GVHD, irradiated BALB/c mice were given B6 alloSCT and T cells. Some mice received IL-12p40 neutralizing Ab or control Ab alone, with or without concurrent IL-33 administration. To test the impact of lymphopenia on T cells, ST2−Foxp3−CD4+ T cells alone or with ST2+ Treg were transferred into B6 Rag2−/−γc−/− mice. Mice received PBS or IL-33 on days 1–8. Neutralizing IL-12 did not reduce ST2 on T cells after alloSCT nor rescue mice from IL-33-mediated acceleration of GVHD. Post-alloSCT, IL-33 worked with IL-12 to expand ST2+Tbet+ Th1 cells. Neutralizing IL-12, but not delivery of IL-33, increased Gata3+ Th2 cells after alloSCT. During LIP, CD4+Foxp3− T cells rapidly upregulated ST2 independent of IL-33, but IL-33 then favored the expansion of Th1 cells, even in the presence of ST2+ Treg. These data suggest that CD4+ T cells rapidly upregulate ST2 during alloSCT conditioning induced lymphopenia. After alloSCT, IL-33 does not support Treg or Th2 cells, but works with IL-12 to augment Th1 responses and GVHD. Blocking stimuli that induces ST2 on proliferating donor CD4+ T cells may be effective for limiting GVHD.
Graft dendritic cell p40 homodimers activate donor-reactive endogenous memory CD8 T cells within higher risk allografts
Authors: Fairchild Robert L. , Tsuda Hidetoshi , Valujskikh Anna 
Published: January 2023

Abstract
Memory T cells with donor-reactivity pose a major barrier to successful transplantation and tolerance induction. Longer cold ischemic storage (CIS) prior to transplantation promotes endogenous donor-reactive memory CD8 T cell infiltration and activation within cardiac allografts to directly mediate CTLA-4Ig-resistant rejection between days 15–22 post-transplant vs. &gt; 60 days for allografts subjected to minimal CIS. Using BrdU labeling, graftinfiltrating memory CD4 and CD8 T cells proliferated much more strongly within allografts subjected to 8 vs. 0.5 hr CIS and proliferation of endogenous memory CD8 T cells within the higher risk allografts required recipient CD4 T cells, graft dendritic cells (DC) and graft expression of class II MHC, CD40 and IL-12p40, but not p35. IL-12p40 but not IL-12 p35 or IL-23p19 mRNA was elevated at 48 hr post-transplant in allografts subjected to 8 vs. 0.5 hr CIS and the increase in p40 mRNA was reduced to the levels seen in 0.5 CIS allografts by recipient CD4 T cell depletion, but was restored by treating with agonist anti-CD40 mAb. p40 homodimers, but not p70 heterodimers, were increased in allografts subjected to 8 hr CIS and were dependent on recipient CD4 T cells. Peri-transplant anti-p40 mAb reversed CTLA-4Ig-resistant rejection of higher risk allografts and peri-transplant p40 homodimers induced endogenous memory CD8 T cell proliferation within allografts subjected to 0.5 hr CIS to the levels observed in allografts subjected to 8 hr CIS. These data indicate that endogenous memory CD8 T cell activation within higher risk cardiac allografts requires CD4 T cell help via CD40-CD154 interactions with graft DC to induce their production of p40 homodimers.
The impact of androgens on neutrophils and melanoma tumor burden.
Authors: Markman Janet , Wakita Daiko , Crother Timothy R. , Arditi Moshe 
Published: January 2023

Abstract

Background
Aged men have increasingly higher incidence of melanoma compared with women and continuously decreasing testosterone (T). Investigation into the mechanism underlying the sex disparity is warranted as there is a low survival rate for metastatic melanoma patients, especially in men.

Methods
We used B16 and YUMM melanoma lung metastatic models. Neutrophils or NK depletion and ovariectomy or castrations were performed. Neutrophils from prostate cancer patients were analyzed.

Data
Compared with males, female mice with melanoma have higher lung tumor burden, reduced neutrophil infiltration, and decreased NK cell activation. While ovariectomy did not affect tumor burden, castrated males had increased lung metastasis and reduced survival compared with sham, suggesting a protective role for T. Further, T replacement in castrated mice reduced metastasis to sham levels. Depletion of NK cells increased tumor burden in male and female mice in a sex independent manner. In contrast, neutrophil depletion increased tumor burden only in males, suggesting a sex difference in neutrophils. More immature neutrophils with impaired function were observed in both castrated mice and prostate cancer patients on androgen ablation therapy.

Conclusion
Our data indicate that innate immunity is important for the response against melanoma colonization of the lung. Neutrophil depletion and castration data suggest a sex specific response which may contribute to the sex disparity observed in human melanoma incidence and survival. Finally, prostate cancer patients on androgen ablation therapy show a similar decrease in mature neutrophils and impaired neutrophil function, which may put these patients at a higher risk for infection and melanoma.
CD103 expression by DCs: a new player in lung cancer immunity.
Authors: Brassard Julyanne , Bernatchez Emilie , Langlois Anick , Blanchet Marie-Renée 
Published: January 2023

Abstract
Despite the use of various therapies, lung cancer remains one of the world’s leading causes of death. Cancer immunotherapy is a promising therapeutic avenue, however, molecular and cellular mechanisms involved in cancer immunity remain elusive. Dendritic cells (DCs), which play an important role in CD8+ T cell activation in cancer immunity, can be divided into two major populations, namely DC1 and DC2, and respectively identified by XCR1/CD103 and Sirpα/CD11b expression. Importantly, studies have demonstrated that DC1s promote cancer immune responses. Furthermore, CD103+ DC1s specialize in the transport of tumor antigens to draining lymph nodes and cross-presentation. However, the influence of the cancer environment, where inflammatory factors (such as TNF) and various inflammatory cells are found, on CD103 expression by DC has never been studied. To verify whether lung cancer-induced inflammation modulates CD103 DC population, fresh lung and splenic DCs were isolated in wild type (WT) mice and exposed to GM-CSF (a known inducer of CD103 expression in the lung) with or without TNF. Furthermore, to directly assess the impact of lung cancer on CD103 DC expression, WT mice were euthanized 2 and 3 weeks following intravenous injection of Lewis lung carcinoma (LLC) cells and the percentage of CD103+DC1 was analyzed in lungs. Exposure to TNF blocked the GM-CSF-induced CD103 expression by DCs, independently of the timing at which TNF is added to cultures (before or after GM-CSF). Also, the % of CD103+ DCs gradually decreased in time following LLC injection. This suggests a new mechanism by which lung cancer negatively impacts the function of immune cells to promote cancer development, and could lead to new therapeutic avenues in cancer immunity.