bluuebunny/crossref_metadata_2025_split huggingface dataset:
Insulin-like growth factor 1 regulates a pulmonary niche promoting type 3 innate lymphoid cell development necessary for protection against pneumonia in the newborn
Authors: Gray Jerilyn Kaye , Oehrle Katherine , Acker Elizabeth Grace , Lang Ian , Cloud Natalee , Deshmukh Hitesh 
Published: January 2023

Abstract
Bacterial pneumonia kills more than a million infants worldwide each year. Type 3 innate lymphoid cells (ILC3) are critical for lung mucosal defense against bacterial pneumonia in the neonatal period when T-cell mediated immunity is weak. The signals that guide the development of pulmonary ILC3 remain incompletely understood. Bone marrow-derived ILC3 are proposed to populate the lungs. We demonstrate that neonatal lung is the principal site of pulmonary ILC3 biogenesis. Mature pulmonary ILC3 are derived from ILC precursors that populate a spatially distinct niche, defined by fibroblasts in developing alveoli. Insulin-like growth factor (IGF) 1, produced by alveolar fibroblasts, instructed expansion and maturation of pulmonary ILC precursors throughout infancy. Conditional ablation of IGF1 in alveolar fibroblasts during postnatal development or deletion of the IGF-1 receptor from ILC precursors interrupted ILC3 biogenesis and rendered newborn mice susceptible to pneumonia. Finally, we show that developmental signals active in alveolar fibroblasts link the postnatal lung development with the expansion and maturation of pulmonary ILC3s, thus coordinating the simultaneous development of lungs and pulmonary mucosal defenses. Accordingly, premature infants with bronchopulmonary dysplasia, a disorder characterized by interrupted postnatal alveolar development and increased morbidity to respiratory infections, had reduced levels of IGF1 and pulmonary ILC3. These data highlight the importance of newborn period as ‘critical window’ in the development of pulmonary mucosal immunity and explain why disrupted lung development in prematurely born infants has an enduring effect on host resistance to respiratory infections.
Type 1 interferon expression and signaling occur in spatially-distinct regions in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques
Authors: Mattila Joshua T 
Published: January 2023

Abstract
Type 1 interferons (IFN1s) are implicated in the pathogenesis of tuberculosis (TB), a disease caused by infection with Mycobacterium tuberculosis (Mtb). Most of the human data on IFN1 in TB come from transcriptional profiling on peripheral blood or human airway cells, but little is known about IFN1 expression or signaling in granulomas, the multicellular lesions associated with TB. Identifying which cells express, or are regulated by, IFN1 in granulomas may enable IFN1-targeting host directed therapies in TB to improve outcomes in TB. To expand our understanding of IFN1 in TB, we examined granulomas from macaques, nonhuman primates that replicate the pathology and course of human TB, to identify how IFN1 is regulated and expressed at the site of disease. We found that granulomas expressed more interferon-stimulated genes (ISGs) and contained more IFN1 protein than uninfected lung but there was substantial heterogeneity between granulomas, even within the same tissue. Epithelioid macrophages in regions commonly infected with Mtb, and a subset of neutrophils in necrotic granuloma regions, had phospho-IRF3+ nuclei, a transcription factor upstream of IFN1 expression and expressed greater quantities of IFN1 protein than cells in other granuloma regions. In contrast, a subset of cells in the lymphocyte cuff strongly expressed the IFN1 receptor IFNAR1 and expressed MX1, an ISG downstream of IFN1. Alveolar macrophages adjacent to granulomas had diverse IFN1-expressing and IFN1-activated phenotypes. These results indicate that IFN1’s biology differs by granuloma microenvironment and that IFN1 expression may be driven by Mtb antigens in granulomas.
Caspase 11 Negatively Regulates Carbapenem-resistant Klebsiella Pneumoniae (CRKP)-induced Pneumonia
Authors: Ghimire Laxman , Paudel Sagar , Jin Liliang , Jeyaseelan Samithamby 
Published: January 2023

Abstract

Background
CRKP remains one of the major causes of health-care associated infections worldwide. Due to its multi-drug resistance property, host-targeted immunotherapy is a promising alternative to treat CRKP-infections. Caspase11, a non-canonical inflammasome, has been shown to protect against cytosolic bacterial pathogens. However, its role in CRKP-induced pneumonia remains elusive.

Methods
We used C57BL/6 (WT) and Caspase 11 knock out (KO) mice to induce pneumonia by intratracheal inoculation of 108 colony forming units (CFUs) of CRKP per mouse. In E coli-induced pneumonia model, 106 CFUs per mouse was used.

Results
Using a mouse model of CRKP-induced pneumonia, we found that Caspase 11 KO mice were protected from intratracheal CRKP infection. The KO mice had significantly less bacterial burden in lungs and BALF compared to their wild-type counterparts. Total leukocytes and neutrophil recruitment into the air spaces were significantly higher in KO mice. To determine whether the phenotype is specific to CRKP infection, we induced pneumonia in WT and KO mice using E. coli through intratracheal route. Consistent with CRKP model, the KO mice displayed protective phenotype during pulmonary E coli challenge suggesting that the phenotype observed in the KO mice is not specific to single bacterium. Further, the KO mice had less IL-1β, CXCL1, and CXCL2 but higher amount of IL-17A secreted in the lungs suggesting that IL-17A could mediate neutrophil recruitment in the KO mice during pulmonary CRKP infection.

Conclusions
Our findings together demonstrate that Caspase 11 negatively regulates CRKP-induced pneumonia and blocking Caspase 11 could be a potential therapeutic intervention for treating CRKP-infected pneumonic patients.
IL-25 Regulates Alveolar Macrophage Exosome Release in Response to LPS
Authors: Fan Jie , Li Yuehua , Li Zhigang 
Published: January 2023

Abstract

Background
Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary and systemic infection. Alveolar macrophages (AMf) are at the center of the pathogenesis of ALI. Emerging evidence has shown that cell-cell interactions in the lungs play an important regulatory role in the development of acute lung inflammation. However, the exact mechanisms remain poorly addressed. In this study, we explore a novel function of lung epithelial cells (LEPC)-derived IL-25 in the regulation of AMf release of exosomes following LPS stimulation.

Methods
For in vivo experiments, C57BL/6 (WT) and TLR4 knockout (TLR4−/−) mice were treated with LPS (2 mg/kg B.W.) in 0.2 ml saline via intratracheal aerosol administration. Bronchoalveolar lavage fluid was then collected at 0 – 24 h after LPS treatment, and the AMf-derived exosomes were measured. For in vitro studies, LEPC and bone marrow-derived Mf (BMDM) were isolated from WT or TLR4−/− mice, and then cocultured in the Transwell™ system. At 0 – 24 h after the coculture, the BMDM and supernatant were harvested for the measurements of exosomes and cytokines.

Results
We demonstrate that LPS induces AMf release of exosomes, which are then internalized by neighboring Mf to promote TNF-a expression. Secretion of IL-25 from LEPC downregulates Rab27a and Rab27b expression in Mf, resulting in suppressed exosome release, thereby attenuating exosome-induced TNF-a expression and secretion.

Conclusion
These findings reveal a previously unidentified pathway of LEPC-Mf cross-talk, which negatively regulates Mf inflammatory responses to LPS. Modulating IL-25 signaling and targeting exosome release may present a new therapeutic strategy for the treatment of ALI.
Dysregulated CARD9 Signaling in Neutrophils Drives Inflammation in a Mouse Model of Neutrophilic Dermatoses
Authors: Tartey Sarang , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of SHP-1 (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatoses in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. This IL-1α dependent inflammation is mediated through SYK-RIPK1-TAK1-ASK1 kinases in Ptpn6spin mice independent of inflammasome activation. In the current study we have identified previously unknown role for CARD9 signaling as a critical regulator for Ptpn6spin-mediated footpad inflammation. Genetic deletion of CARD9 significantly rescued thePtpn6spin-mediated footpad inflammation. Mechanistically, enhanced IL-1α mediated signaling in Ptpn6spin mice neutrophils was dampened in Ptpn6spinCard9−/−mice. Collectively, this study identifies SHP-1 and CARD9 crosstalk as a novel regulator of IL-1α driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans.
Modeling the stimulatory network of CD16, 2B4 and NKG2D in natural killer cell activation
Authors: Makaryan Sahak Z , Finley Stacey 
Published: January 2023

Abstract
Natural killer (NK) cells are innate immune effector cells that play an immediate role in host defense by releasing cytotoxic chemicals upon activation. A better understanding of the mechanisms regulating NK cell activation can improve NK cell-based therapies. However, due to the diversity of stimulatory pathways, each with a complex network of signaling species, a systems biology approach is required to understand NK cell activation. We constructed a mathematical model that mechanistically describes the signaling network of CD16, 2B4 and NKG2D. The model was fit to published experimental data and validated with a separate dataset. Baseline model predictions demonstrate that CD16 and NKG2D are qualitatively similar in that they activate the downstream species to a greater degree and at a faster rate when compared to 2B4. Contrastingly, 2B4 activates the signaling species over a longer time interval. In silico pairwise co-stimulation of the receptors, using various ligand concentrations, preferentially impacts the kinetics of species activation: the species are activated faster but the time interval of species activation becomes shorter as more ligands are introduced. Perturbing the stimulatory pathways by altering kinase (activator) and phosphatase (inhibitor) activity, highlights the phosphatases’ predominant control of the network and shows that decreasing their level of activity greatly improves the rate of species activation. Thus, the model predicts (1) qualitative differences between the pathways, (2) increasing receptor stimulation impacts the kinetics of species activation and (3) inhibiting the inhibitor significantly augments signal transduction. This insight can help design NK cell immunotherapies.
The suppressor of cytokine signaling 1 (SOCS1) impairs skin host defense in healthy and hyperglycemic mice
Authors: Klopfenstein Nathan , Serezani Henrique 
Published: January 2023

Abstract
Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of skin and soft tissue infections in both healthy individuals and those with preexisting conditions such as diabetes. MRSA skin infections are characterized by the formation of a neutrophilic abscess that prevents bacterial spread to deeper tissues. Although we and others have shown that skin resident macrophages initiate this immune response, the molecular events that lead to optimal neutrophil recruitment and abscess formation remain to be fully elucidated. Here we examined the role of the protein SOCS1 and its impact on host defense during MRSA skin infection in both hyperglycemic and euglycemic mice. SOCS1 is a known STAT1 inhibitor and negatively influences TLR activation, possibly influencing early skin host defense. We have previously demonstrated that hyperglycemic mice are unable to control MRSA skin infection, which was accompanied by poor abscess formation. Here, we demonstrate that SOCS1 expression in macrophages isolated from infected hyperglycemic mice is greatly enhanced in a manner dependent on histone deacetyltransferase (HDAC) activity. Delivery of SOCS1 inhibitor peptide (iKIR) as well as myeloid cell-specific SOCS1 deletion decreased both lesion size and bacterial burden in the skin. SOCS1 inhibition enhanced the production of pro-inflammatory cytokines TNF-a and IL-1b. Importantly, SOCS1 inhibition enhanced bacterial ingestion and killing in macrophages from both euglycemic and hyperglycemic mice. Overall, these data indicate that the threshold of SOCS1 expression may negatively impact skin host defense in both hyperglycemic and other susceptible patient populations.
Lactic acid suppresses LPS-induced mast cell cytokine production by limiting glycolysis and ATP availability
Authors: Ryan John J , Hoeferlin L. Alexis , Chalfant Charles E. , Caslin Heather 
Published: January 2023

Abstract
Sepsis, a life threatening response to infection, has a well-studied initial cytokine storm, with a less understood secondary immunosuppressive phase. Elevated blood lactate and slow lactate clearance are associated with mortality, however, any regulatory role is unknown. We hypothesized that lactic acid contributes to the late phase of sepsis and is not solely a consequence of bacterial infection. Thus far, no studies have examined the effect of lactic acid on sepsis models in vivo or a mechanism by which they suppress LPS activation in vitro. Because mast cells can be activated systemically and contribute to sepsis, we examined lactic acid effects on the mast cell response to the bacterial product LPS. Lactic acid significantly suppressed LPS-induced cytokine production and NFκB-mediated transcription in mouse bone marrow derived mast cells and cytokine production in peritoneal mast cells. Suppressive effects were MCT-1-dependent and observed with sodium lactate or formic acid. Further, lactic acid significantly suppressed cytokine induction following LPS-induced endotoxemia in mice. Because glycolysis is linked to inflammation and lactic acid is a by-product of this process, we examined changes in glucose metabolism. Lactic acid treatment reduced glucose uptake and lactate export during LPS stimulation. Lactic acid effects were mimicked by glycolytic inhibitors and reversed by increasing ATP availability. These results indicate that glycolytic suppression and ATP production are necessary and sufficient for lactic acid effects. Our work suggests that enhancing glycolysis and ATP production could improve immune function, counteracting lactic acid suppressive effects in the immunosuppressive phase of sepsis.
Single-cell analysis of γδ T cells reveals limited TCR delta chain diversity in mouse lung Vγ4 γδ T cells
Authors: Mistri Somen K , Hampel Kenneth J , Dienz Oliver , Boyson Jonathan E 
Published: January 2023

Abstract
γδ T cells are innate-like T cells that are one of the first responders in the defense against pathogens through their rapid production of pro-inflammatory cytokines like IL-17 and IFN-γ. Currently, the mechanisms that direct γδ T cells to exert these distinct effector functions are unknown. The limited TCR diversity of tissue-specific γδ T cells is often associated with specific effector functions. We have recently found that IL-17- and IFN-γ-producing Vγ4 γδ T cells in the lung are marked by SLAM1 and SLAM6 cell surface receptors, respectively. Our long-term goal is to investigate the link between γδ T cell effector function, specific SLAM family receptor expression, and TCR clonotype usage. The objective of this study was to identify the major Vγ4 γδ TCR clonotype(s) in the mouse lung. Vγ4 γδ T cells were single cell-sorted and paired TCR clonotypes were identified using next-generation sequencing of TCR amplicon libraries. Out of 789 sorted lung C57BL/6 Vγ4 T cells, we obtained paired TCR γ and δ chain sequences from 396 cells. These data revealed that Vδ5 and Vδ2 chains accounted for 56.20% and 35.77% of the productive TCRδ chain rearrangements, respectively. A significant fraction of the Vδ5 sequences were characterized by invariant germline-encoded (28.57%) or highly restricted (9.10%) Vδ5Dδ2Jδ1 sequences. Likewise, 55.10% of the Vδ2 sequences were characterized by a highly restricted Vδ2Dδ2Jδ1 sequence. These data reveal that the lung Vγ4 γδ T cell population is characterized by extremely limited delta chain usage. Since lung Vγ4 T γδ cells are programmed to be SLAM1+IL-17+ or SLAM6+IFN-γ+, future studies will determine whether there is a link between this limited TCRδ chain usage, cytokine production, and SLAM receptor expression.
Redox regulation of autophagy in thymic stromal cell function
Authors: Semwal Manpreet Kaur , Hester Allison K , Xiao Yangming , Venables Thomas , Griffith Ann 
Published: January 2023

Abstract
T lymphocytes develop in the thymus, where mutually inductive signaling between lymphoid progenitors and thymic stromal cells directs the progenitors along a well-characterized program of differentiation. However, the biology of the stromal cells comprising the lymphopoietic thymic microenvironment remains relatively under-characterized because stromal cells are rare and difficult to isolate. Using a deconvolution technique to study gene expression essentially in situ, we previously identified a deficiency in the peroxide quenching enzyme catalase (CAT) in thymic stromal cells, and found that CAT deficiency results in high reactive oxygen (ROS) levels in this population, eventually leading to thymic atrophy. Our current studies address the possibility that high ROS levels serve physiological functions in stromal cells in the young, steady-state thymus. Autophagy is critical for self-antigen presentation and T cell selection in the thymus, and is induced by many stressors, including oxidative stress. Our preliminary data indicate that catalase overexpression targeted to mitochondria in transgenic mice (mCAT Tg) results in diminished autophagy in thymic stromal cells and causes diminished negative selection in the thymus. Our results suggest that, while accumulated oxidative damage ultimately undermines healthy thymus function, a high ROS environment in stromal cells promotes autophagy critical for stromal induction of T cell tolerance in the young, steady-state thymus.
Supported by N.I.H. grants R01AI121367 and R21AI103685
Catalase expression mediates redox regulation of promiscuous gene expression in thymic stromal cells
Authors: Hester Allison Katherine , Semwal Manpreet K , Yangming Xiao , Cepeda Sergio , Venables Thomas , Griffith Ann 
Published: January 2023

Abstract
The primary site for the development of T lymphocytes is the thymus, where cross-talk between thymic stromal cells (TSCs) and T cell progenitors mediates the development and maintenance of both populations. However, the thymus begins to atrophy relatively early in life, resulting in diminished T cell output, and corresponding immunodeficiencies in aged individuals. Our previous studies revealed that thymic stromal cells express conspicuously low levels of the peroxide quenching enzyme catalase (CAT), which results in high reactive oxygen species (ROS) levels and accumulated oxidative damage in thymic stromal cells, ultimately promoting thymic atrophy. In our current studies, we find that when catalase deficiency is complemented by overexpression targeted to mitochondria in transgenic mice (mCAT Tg), stromal function declines in young mice relative to non-transgenic littermates. TSC transcriptome analysis reveals decreased expression of tissue-restricted antigen (TRA) genes in young mCat Tg mice relative to controls. Stromal TRA expression is required for self-antigen presentation, and therefore promotes negative selection of potentially auto-reactive T cells. We propose that oxidative stress generated by low catalase levels in stromal cells promotes this key physiological function in the young, steady state thymus; in contrast however, the resulting accumulated oxidative damage ultimately impairs function in the aged thymus.
Identification and characterization of lung commensal bacteria that modulate immune response in Tuberculosis
Authors: Bernard Lucie , Colom André , Cescato Margaux , Cougoule Céline , Guilloton Pauline , Ghebrendrias Natsinet , Capilla Florence , Alloy Annie , Remot Aude , Thomas Muriel , Langella Philippe , Neyrolles Olivier , Lugo-Villarino Geanncarlo 
Published: January 2023

Abstract
Tuberculosis (TB) is still one of the deadliest infectious diseases in humans. As TB disease is driven by exacerbation of the immune response, promising approaches include host-targeting therapies aiming at controlling the balance between pathogen eradication and limitation of the inflammation in order to prevent immunopathology. Such immune modulation has been observed through modification of the gut-microbiota compartment with oral administration of specific bacterial strains (i.e. probiotics) in other respiratory diseases. In TB, a dysbiosis of the microbiota is observed in patients, and microbiota perturbation in mice increases susceptibility to Mycobacterium tuberculosis (Mtb). Here, we assessed whether bacterial strains isolated from the recently described lung microbiota could have a local impact on Mtb infection by protecting against immune dysfunction for the host benefit. Through intranasal administration in mice, we identified different microbiota strains isolated from mouse lungs with a strong ability to modulate the lung T cell compartment. The same in vivo approach in Mtb-infected mice revealed one strain with a remarkable capacity to diminish Mtb infection-associated lung immunopathology, accompanied by a specific immune signature characterized by an increase level of regulatory T cells sharing surprisingly T-helper 17 cell markers. Collectively, this work may contribute to the design of host-directed therapies to reduce the destructive inflammatory response in TB, without further fomenting the occurrence of multiple-drug resistant Mtb strains. It will also shed light on poorly described populations in the lungs such as the RORgt+ Foxp3+ biTregs and their interactions with the microbiota.
Repeated respiratory bacterial exposures elicit lung resident memory B cells in the absence of organized tertiary lymphoid tissue
Authors: Barker Kimberly A , Smith Nicole M , Shenoy Anukul T , Martin Ian MC , Jones Matthew R , Quinton Lee J , Mizgerd Joseph P. 
Published: January 2023

Abstract
Recent work has shown that resident memory B cells (BRM) are generated in the lung after flu infection. However, it is unclear whether the existence of lung BRM is unique to influenza, which often elicits iBALT, or alternatively if these cells represent a common feature of the lung immune landscape. We aimed to determine whether bacterial lung exposures experienced by nearly all human children might also elicit lung BRM. To model this scenario, we gave young mice repeated respiratory exposures to low virulence pneumococci. After at least 4 weeks, we then analyzed lung B cells using flow cytometry and an intravital CD45 stain to exclude intravascular leukocytes. Pneumococcus-exposed mice had many more extravascular IgD- lung B cells than controls, and these B cells remained in the lung at least 12 weeks after the last exposure. Although unorganized aggregates of B and T cells were observed in previously exposed lungs, no iBALT structures were generated. Most of the IgD-B cells expressed the memory markers PD-L2, CD80, and CD73; a majority of the B cells expressed two or more of these markers, indicating they are poised to become antibody secreting upon rechallenge. Notably, the hallmark lung TRM phenotype (CD11abrightCD69+CD44brightCD62Llow) was also observed on lung B cells; these markers may represent a common resident memory lymphocyte phenotype. Although all lung B cells were CD20+, they were not affected by αCD20 antibody treatment, which requires circulation of bound cells for depletion to occur. BRM appear to be a common feature of the adaptive immune cell repertoire of experienced lungs. These cells do not require iBALT for their maintenance and represent a previously unrecognized pool of B cells resistant to depletion with αCD20 therapy.