bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrin αv limits TLR signaling in plasmacytoid dendritic cells
Authors: Lorant Alina K , Lacy-Hulbert Adam 
Published: January 2023

Abstract
SLE is a chronic, systemic autoimmune disease affecting millions of people worldwide. SLE is caused by a breakdown of tolerance to self-derived nucleic acids (NA) and characterized by the presence of autoantibodies to DNA/RNA. Plasmacytoid dendritic cells (pDCs) are highly tuned to respond to NA and express a range of receptors for RNA and DNA, including TLRs 7 and 9. Following TLR engagement, pDCs produce high levels of type I interferon (IFN-I), which promotes loss of tolerance, implicating pDCs in development of autoimmunity. However, relatively little is known about how innate immune signaling is regulated in pDCs, and particularly how they distinguish self-derived from foreign NA.
TLRs 7 and 9 are both localized in endosomal compartments, and their NA ligands must be internalized and processed before they can bind. One source of these NA is dying cells and loss of their receptors is associated with SLE. We studied the role of an apoptotic cell receptor, Integrin αv, in TLR signaling of pDCs and found that αv limits IFN-I production. In mice without αv, there is a systemic increase in IFN-I and inflammatory cytokines after TLR7 stimulation. This corresponds with an increase in pDC activation and the number of IFN-I-producing pDCs in the spleen. αv-knockout pDCs show increased TLR signaling and produce more IFN-I and inflammatory cytokines when stimulated in culture.
These data indicate αv has a pDC-intrinsic role in limiting TLR signaling, which we propose is through activation of non-canonical autophagy. Based on these data, we hypothesize that co-receptors involved in capture and internalization of nucleic acids provide contextual ‘cues’ to regulate TLR signaling and prevent autoimmunity.
Complement activation by C-reactive protein is essential for protection against pneumococcal infection
Authors: Singh Sanjay Kumar , Ngwa Donald N , Agrawal Alok 
Published: January 2023

Abstract
C-reactive protein (CRP), a component of the innate immune system, is an antimicrobial plasma protein. The primary ligand-binding specificity of CRP is for phosphocholine-containing substances and ligand-complexed human CRP activates the complement system in both human and mouse sera. It has been shown that human CRP protects mice against infection with lethal doses of Streptococcus pneumoniae; the protection is due to CRP-dependent decrease in bacteremia and increase in survival time. In this study, we tested a decades old hypothesis that the complement-activating function of ligand-complexed CRP contributes to protection of mice against pneumococcal infection. We employed site-directed mutagenesis of CRP, guided by its three-dimensional structure, and identified a mutant H38R which, unlike wild-type CRP, did not activate C3 in both human and mouse sera. The calcium-dependent binding to phosphocholine on pneumococci, the half-life in mouse circulation, and the overall pentameric structure of H38R mutant CRP were similar to that of wild-type CRP. Employing a murine model of pneumococcal infection, we found that passively administered H38R mutant CRP did not protect mice from infection. Infected mice injected with H38R mutant CRP showed no reduction in bacteremia and did not survive longer, as opposed to infected mice receiving wild-type CRP. Thus, the hypothesis that complement activation by ligand-complexed CRP is an antimicrobial effector function is true. We conclude that complement activation by ligand-complexed CRP is essential for CRP-mediated protection against pneumococcal infection. (NIH AI117730)
Staphylococcus aureus biofilm-derived lactate inhibits HDAC11 to augment leukocyte IL-10 production and promote infection persistence
Authors: Heim Cortney , Bosch Megan E , Yamada Kelsey J , Aldrich Amy L , Chaudhari Sujata S , Klinkebiel David , Gries Casey M , Alqarzaee Abdulelah A , Li Yixuan , Seto Edward , Karpf Adam R , Kielian Tammy 
Published: January 2023

Abstract
Staphylococcus aureus (S. aureus) is a leading cause of biofilm-associated prosthetic joint infections (PJIs), where leukocyte IL-10 production is critical for biofilm persistence. We screened a S. aureus mutant library that identified the importance of lactate biosynthetic pathways to elicit IL-10 production. A S. aureus Δddh/ldh1/ldh2 mutant, defective in both D- and L-lactate production, led to significantly decreased leukocyte IL-10 expression and re-programmed biofilm-associated monocytes to a pro-inflammatory state, resulting in reduced biofilm burden. Histone acetylation plays a central role in regulating gene expression, and we found that histone deacetylase (HDAC) activity was increased in Δddh/ldh1/ldh2-infected mice compared to WT concomitant with significant decreases in global histone 3 (H3) acetylation and H3 acetylation at the IL-10 promoter, demonstrating that S. aureus-derived lactate is a HDAC inhibitor. Lactate was found to inhibit HDAC11, which resulted in unregulated HDAC6 activity and increased IL-10 production. MDSCs and macrophages produced significantly less IL-10 in the presence of the HDAC6 inhibitor tubastatin A during co-culture with WT but not Δddh/ldh1/ldh2 biofilms, while HDAC11 KO MDSCs and macrophages co-cultured with Δddh/ldh1/ldh2 biofilms produced significantly more IL-10 compared to WT cells due to unchecked HDAC6 action. D-lactate was elevated in synovial fluid of patients with PJI compared to aseptic controls and lactate also promoted IL-10 production by human monocyte-derived macrophages. Collectively, S. aureus lactate-mediated inhibition of HDAC11 plays a critical role during biofilm infection, leading to epigenetic changes that reprogram the host immune response.
Suppression of caspase-11-mediated cytosolic LPS sensing pathway by Shiga toxin
Authors: Mendonça Morena , Ta Atri , Russo Ashley , Behl Bharat , Rathinam Vijay , Vanaja Sivapriya Kailasan 
Published: January 2023

Abstract
Enterohemorrhagic Escherichia coli (EHEC) serotype O157:H7 is a human pathogen that causes hemorrhagic colitis and hemolytic uremic syndrome (HUS). Shiga toxin (Stx), the primary virulence factor of EHEC, mediates much of the morbidity and mortality associated with EHEC infection. Although Stx is well characterized in terms of its toxic activity, it is not clear if Stx has a specific role in immune cells during EHEC infection. In this study, we identified an inflammasome inhibitory role for Stx during EHEC infection. Stx specifically suppressed the activation of caspase-11-mediated cytosolic LPS sensing pathway in macrophages and mice. Stx did not inhibit the production of inflammasome-independent cytokines, TNF and IL-6. Similarly, Stx did not impair the activation of AIM2, NLRC4, or the canonical NLRP3 inflammasomes. Multiples subtypes of stx were able to suppress the caspase-11-mediated inflammasome responses. Stx was also capable of suppressing inflammasome responses induced by intraperitoneal injection of LPS as well as by Citrobacter rodentium infection in mice. Together, these data reveal that Stx plays an important role in overcoming inflammasome responses during EHEC infection.
Regulatory T cells integrate combinatorial cytokine signaling to promote immune homeostasis
Authors: Zhou Julie Y , Alvarez Carlos A , Cobb Brian A 
Published: January 2023

Abstract
The increasing prevalence of inflammatory and autoimmune diseases worldwide fuels a growing need to develop new therapeutics. Here we identify and adopt a strategy utilized by a common commensal microbe, Bacteroides fragilis, to induce immune homeostasis, by which its dominant antigen Polysaccharide A (PSA) drives classical MHCII:αβTCR engagement and elicits a strong IL-10 response via effector memory T cell (Tem) to regulatory T cell (Treg) communication. We recently discovered that IL-2 and IL-4 are critical factors driving PSA-initiated Tem-&gt;Treg communication. By tracking Tregs isolated from novel FoxP3RFP/IL-10GFP mice over time, we reveal here that these cytokines in combination elicit a profoundly divergent response from that of single cytokine stimulation. The Tregs resulting from combinatorial cytokine stimulation were more IL-10 expressing and proliferative, with IL-10+ Tregs expanding preferentially. We found that these Tregs were more effective in suppressing the proinflammatory behavior of conventional T cells, with changes in STAT5 and STAT6 signaling appearing to underlie this response. The robust effect of the combinatorial cytokines is further illustrated by their ability to suppress both HDM-induced asthma and experimental autoimmune encephalomyelitis (EAE), including clinical score, demyelination, MOG-specific conventional T cells, and production of pathogenic IL-17A in preventative, concomitant, and therapeutic delivery schedules. These data indicate that Tregs integrate multiple cytokine signaling to produce a biological outcome divergent from the two individual cytokines, and that this phenomenon holds therapeutic promise for multiple inflammatory and autoimmune diseases.
Sub-lethal Dose of Alcohol Modulates Innate Immune-Mediated Regulatory T-Cell Differentiation
Authors: Sharma Apoorv R , Venkatadri Rajkumar , Sabapathy Vikram , Mohammad Saleh , Sharma Rahul 
Published: January 2023

Abstract
The use of alcohol for consumption and other purposes is widely prevalent in our society. High concentration of alcohol (ethanol) in the household and clinical cleaners is employed for disinfecting. Deleterious effects of alcohol abuse in terms of death and dysfunction of cells, including immune-cells, has been extensively documented. However, moderate consumption of alcoholic beverages has been indicated to be beneficial. In this study, we sought to investigate the effects of sub-lethal doses of alcohol on the interaction of innate and adaptive immunity. We used murine bone marrow-derived macrophages (BMM) as antigen presenting cells and naïve T-cells isolated from spleens of C57BL/6 mice for in vitro T-helper differentiation assays. We found that doses of alcohol at 3% (v/v) or higher induces severe cell death, whereas lower concentrations of alcohol (&lt;2% v/v) modulates the BMM activity for increased differentiation of T-regulatory cells (Tregs), which play a major role in preventing inflammation. Further, alcohol at lower doses also reversed the inhibitory effect of the endotoxin lipopolysaccharide (LPS) on Treg differentiation. Interestingly, BMM treated with alcohol also increased differentiation of TH17 cells. We also investigated the effects of alcohol-treated BMM on immune-modulation of T-helper differentiation in vivo. The data provide insights for immunomodulatory effects of low doses of alcohol and have implications for the regulation of Tregs.
Examining immunological tolerance through the lens of reproduction
Authors: Kinder Jeremy Michael , Way Sing Sing 
Published: January 2023

Abstract
Pregnancy is generally considered an “immunological conundrum” whereby a mother must circumvent immunological rules dictating binary “self” vs “non-self” antigen distinction to tolerate her genetically-foreign baby. However, considering reproductive success is the primary biological imperative for all species, it has likely served as an important driver of immune development across mammalian evolution. In other words, reproductive tolerance is not an exception to these rules but serves as a selective pressure continually refining our immune development. To this end, we have begun investigating the long-term impacts of the bi-directional exchange of intact maternal and fetal cells during pregnancy that persist systemically at low, microchimeric levels in mother and child decades after delivery. We believe these genetically-foreign microchimeric cells are not accidental souvenirs of pregnancy, but are instead intentionally preserved to promote tolerogenic memory to both fetal-paternal and non-inherited maternal alloantigens encountered during pregnancy. Thus, we have developed animal pregnancy models and cutting-edge tools that allow selective manipulation of maternal and fetal microchimeric cells together with dynamic tracking of antigen-specific immune responsiveness to these genetically-foreign cells during and after pregnancy. Viewing reproductive success as a strong driver of our immunological evolution, uncovering tolerance mechanisms employed during and after pregnancy will not only inform strategies for amelioration of pregnancy complications but applies in other clinical settings where the ability to regulate immune tolerance is desired (e.g. transplantation, cancer, persistent infection).
A Neural Circuit for the Suppression of Peripheral Inflammation by Hunger
Authors: Klima Michelle , Alhadeff Amber , Kruger Kayla , Pulido Santiago , McKnight Aaron , Betley J. Nicholas 
Published: January 2023

Abstract
Hunger is a primal biological drive that can initiate behavioral changes. Intuitively, hunger can inhibit behaviors such as sleep while simultaneously promoting foraging. Because pain can prevent an animal from seeking food we questioned if hunger could suppress pain. We found that food deprived mice reduce their response to inflammatory nociceptive stimuli. This reduction in nocifensive behavior during hunger is specific to inflammatory pain as the response to acute thermal and mechanical nociceptive stimuli remains intact. During hunger, agouti-related protein expressing (AgRP) neurons in the hypothalamus become active. AgRP neuron activation is both necessary and sufficient for feeding behavior and is thus a way to model hunger without the peripheral complications. Importantly, activating AgRP neurons recapitulates the analgesic effects of hunger.
Because food deprivation reduces inflammatory pain responses, we next explored the influence of hunger and AgRP neuron activity on peripheral inflammation. To address this question, we measured paws after an injection of Complete Freund’s Adjuvant (CFA) in food deprived mice. We found that food deprivation was able to reduce CFA-induced paw inflammation compared to ad libitum fed controls. To assess the role of the AgRP circuit on inflammation, we measured CFA injected paws during optogenetic stimulation of AgRP neurons. Optogenetic activation of AgRP neurons rapidly reduces paw inflammation. This rapid and robust reduction in peripheral inflammation following activity in a CNS circuit suggests that AgRP neuron activity interacts with the immune system. Current experiments are aimed to determine the CNS à immune pathway that quickly reduces peripheral inflammation.
Divergent roles of retinoic acid signaling in T regulatory cell function
Authors: Thangavelu Govindarajan , Andrejeva Gabriela , Loschi Michael , Aguilar Ethan G , Lee Yu-Chi , Furlan Scott N , McDonald-Hyman Cameron , Zaiken Michael C , Feser Colby J , Panoskaltsis-Mortari Angela , Kean Leslie S , Rathmell Jeffrey C , Chi Hongbo , Noelle Randolph J , Blazar Bruce R 
Published: January 2023

Abstract
Regulatory T cells (Tregs) modulate immune responses to maintain immune homeostasis. Retinoic acid (RA) signaling promotes Treg generation and stability. Paradoxically, we observed that dominant negative RA receptor α expressed only in donor T cells (DNRARαfl/flCD4Cre) dampened inflammation and graft-versus-host disease (GVHD), while increasing Tregs. We found that diminishing RA signaling significantly enhanced their in vitro suppressive capacity. In vivo the adoptive transfer of DNRARαfl/flCD4Cre Tregs at the time of transplant was significantly (p&lt;0.01) more effective than wild type (WT) controls in ameliorating GVHD. Mechanistically, enhanced suppression was associated with elevated expression of suppressive (CTLA-4, GITR, CD39) and fitness (CD25, pSTAT5) markers. To evaluate the intrinsic requirement of RA signaling in Tregs, we generated transgenic mice with conditional DNRARα expression in Tregs (DNRARαfl/fl x Foxp3YFPCre). Surprisingly, the extent of ablation of RA signaling resulted in divergent phenotypes. Heterozygous ablation (DNRARαfl/wt) was permissive of enhanced Treg suppression. In striking contrast and unexpectedly, homozygous ablation (DNRARαfl/fl) impaired Treg suppressive function and caused multi-organ (lung, liver) autoimmunity in &gt;90% of females and males by 3 months of age. Poor suppression is not cell intrinsic as DNRARαfl/fl Tregs isolated from mixed bone marrow chimeras of congenic WT and DNRARαfl/fl x Foxp3YFP Cre had enhanced function. Our studies indicate that RA signaling in Tregs can be targeted to prevent autoimmunity by enhancing Treg suppression or alternatively, promote antitumor responses by reducing Treg function.
Increased regulatory T cells suppress traumatic injury induced inflammation and control adaptive immune cell expansion in an experimental model of burn trauma
Authors: Cahill Laura , Guo Fei , Zhang Fan , Ng Julie , Griffith Alec , Howard Kaitlyn , Keegan Joshua , Lederer James 
Published: January 2023

Abstract
Trauma-induced inflammatory dysfunction is a lesser appreciated field of conventional immunology. In fact, traumatic injury is the leading cause of death in the US for people under 44 years old and resultantly disrupts immune homeostasis that puts injured patients at risk for developing opportunistic infections and succumbing to post-injury sepsis. Regulatory T cells (Tregs) are unique cells that contribute to immune balance but play a key role in the undesirable post-trauma immune suppression by repressing important Th-1 type immunity. Interestingly however, several reports demonstrate that Tregs confer a survival advantage in trauma. Therefore, it raises the question, do injured patients with quantitively enhanced Tregs fare better than those with less Tregs? Accordingly, we examined the role of increased Tregs on immune cell subsets in a murine burn-trauma model.
C57BL/6 mice were treated with anti-DR3 to increase Tregs before burn trauma. Mice treated with anti-DR3 prior to burn and secondary pseudomonas aeruginosa infection showed improved survival compared with untreated mice. CyTOF analysis revealed burn-injured mice given anti-DR3 showed increased counts of Ki-67+ splenic PMN-MDSCs compared to sham and burn-injured control mice. This corresponded with higher levels of PMN chemoattractants by stimulated splenocytes from burn-injured mice given DR3. Sham and burn-injured mice with higher Tregs also had increased numbers of activated γδ T cells compared to untreated mice, suggesting that these cells are regulated by an increase in Tregs. This study indicates that in trauma, it may be necessary to maintain high Treg levels to alleviate trauma-induced immune dysregulation and restore immune homeostasis.
Super-induction of immunosuppressive glioblastoma extracellular vesicles by IFN-g through PD-L1 and IDO1
Authors: Jung Mi-Yeon , Brown Desmond A. , Himes Benjamin , Garcia Luz Milbeth Cumba , Parney Ian F. 
Published: January 2023

Abstract
Glioblastoma is the most common and aggressive primary brain tumor. Median survival is 15 months despite surgery, radiation, and chemotherapy. Immunotherapy is promising but glioblastoma-mediated immunosuppression remains a barrier. Recently, extracellular vesicles (EVs) have been implicated in glioblastoma-mediated immunosuppression through expression of the immune checkpoint molecules PD-L1 and IDO1 which have been implicated in T cell function suppression and decreased proliferation in some cancers. Our data demonstrate that PD-L1 and IDO1 expression are increased in most nucleated cells following IFN-γ exposure. IFN-γ exposure did not alter EV production or expression of common EV markers but increased PD-L1 and IDO1 expression in EVs from differentiated but not stem-like GBM cells. Differentiated glioblastoma cell derived EVs induced myeloid-derived suppressor cell and non-classical monocyte differentiation from normal monocytes. This was increased following IFN-γ exposure and was dependent upon both PD-L1 and IDO1 expression but not stem-like GBM cell. Monocytes exposed to differentiated but not stem-like GBM cell EVs inhibited T cell proliferation in a similar manner (increased with IFN-γ exposure, decreased with PD-L1 or IDO1 knockdown). Thus, IFN-γ exposure results in super-induction of immunosuppressive EVs from differentiated but not stem-like GBM cells that increase MDSC and NCM differentiation in normal monocytes and increase their ability to inhibit T cell proliferation. These effects are dependent upon PD-L1 and IDO1 up-regulation induced by IFN-γ. This may be an important mechanism GBMs utilize to suppress anti-tumor T cell responses that are typically accompanied by increased IFN-γ expression.
Immunological function of Foxo6 in hypersensitive immune reaction
Authors: Kim Mi Eun , Lee Jun Sik 
Published: January 2023

Abstract
Forkhead box O(FoxO) is a transcription factor which is involved in cell cycle progression, cell survival and DNA-repair. Dendritic cells(DCs) are professional antigen-presenting cells which present the antigens to T lymphocytes and regulate the adaptive immunity. Previous studies indicated that FoxO1 and 3 are plays a critical role in DC maturation and DC-T cell interaction. FoxO6, a member of FoxO family, is less attended than other FoxO families, because limited expression region of FoxO6. Also, the effect of FoxO6 is still unknown. Here, we investigated the effect of FoxO6 in dendritic cells. Phosphorylated FoxO6 is increased and acetylated FoxO6 is decreased during dendritic cell differentiation. Moreover, deficiency of Foxo6 altered antigen capacity of dendiritc cells. Therefore, we expect that FoxO6 has important role in DC differentiation and maturation, and will further investigate the functions and the mechanisms of FoxO6 on DC. And alteration of FoxO6 expression level had effect on DCs maturation.
Lymphotoxin β receptor signaling and CD11c-positive dendritic cells form high endothelial venule-like vessels in the skin in murine atopic dermatitis model
Authors: Kanameishi Shuto , Ono Sachiko , Honda Tetsuya , Kabashima Kenji 
Published: January 2023

Abstract
High endothelial venules (HEVs), which are characterized by the expression of peripheral node addressin (PNAd), are essential routes for the trafficking of naïve T cells and central memory T cells (Tcms) into secondary lymphoid organs. In lymph nodes (LNs), lymphotoxin (LT) α1β2-LTβ receptor (LTβR) signaling from dendritic cells (DCs) is essential for the formation of HEVs. Although it has been reported that PNAd+ HEV-like vessels appear in the skin under some inflammatory condition, such as atopic dermatitis (AD), the formation mechanism of HEV-like vessels and their functions in the skin have remained unclear.
To clarify these issues, we established a system to induce PNAd+ HEV-like vessels in the skin, using a mouse AD model induced by calcipotriol. Flow cytometric (FCM) analysis revealed that around 20–30% of vessels were PNAd+ in the AD-like skin lesions. Electron microscopic analysis showed prominent formation of rough endoplasmic reticulum, Golgi apparatus and mitochondria in the HEV-like vessels similar to HEVs in LNs. These vessels were mainly detected in post-capillary venules, around which dermal DCs formed clusters. Administration of LTβR-Fc fusion protein or inhibition of the DC clusters by either pertussis toxin or depletion of DCs using CD11c diphtheria toxin receptor transgenic mice abolished the formation of HEV-like vessels in the skin. Naïve T cells and Tcms infiltration were detected in both AD patients and murine AD model skin by immunohistochemistry and FCM.
Collectively, our results suggest that LTβR signaling and CD11c+ DCs mediate the formation of HEV-like vessels in the skin, which may possess functions of HEV and regulate the transmigration of naïve T cells and Tcms.