Extra-pulmonary control of respiratory defense.

Pneumonia persists as a public health crisis, representing the leading cause of death due to infection. Whether respiratory tract infections progress to pneumonia and its sequelae such as acute respiratory distress syndrome and sepsis depends on numerous underlying conditions related to both the causative agent and host. Regarding the former, pneumonia burden remains staggeringly high, despite the effectiveness of pathogen-targeting strategies such as vaccines and antibiotics. This demands a greater understanding of host features that collaborate to promote immune resistance and tissue resilience in the infected lung. Such features inside the pulmonary compartment have drawn much attention, where major advances have been made related to resident and recruited immune activity. By comparison, extra-pulmonary processes guiding pneumonia susceptibility are relatively elusive, constituting the focus of this review. Here we will highlight examples of when, how, and why tissues outside of the lungs dispatch signals that modulate local immunity in the airspaces. Topics include the liver, gut, bone marrow, brain and more, all of which contribute in direct and indirect ways to pneumonia outcome. When tuned appropriately, it has become clear that these responses can serve protective roles, and this will be considered distinctly from what would otherwise be aberrant responses characteristic of pneumonia-induced organ injury and sepsis. Further advances in this area may reveal novel targetable areas for clinical intervention that are not confined to the intra-pulmonary space.

Endothelial cell expression of a STING gain-of-function mutation initiates pulmonary lymphocytic infiltration.

Patients afflicted with Stimulator of interferon gene (STING) gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154M mutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in initiating ILD. To identify STING-expressing non-hematopoietic cell types required for the development of ILD, we use a conditional knockin (CKI) model and direct expression of the VM allele to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted VM expression results in enhanced recruitment of immune cells to the lung associated with elevated chemokine expression and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of STING-associated vasculopathy with onset in infancy (SAVI) patients or patients afflicted with other ILD-related disorders.

Using urine FTIR spectra to screen autism spectrum disorder.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder caused by multiple factors, lacking clear biomarkers. Diagnosing ASD still relies on behavioural and developmental signs and usually requires lengthy observation periods, all of which are demanding for both clinicians and parents. Although many studies have revealed valuable knowledge in this field, no clearly defined, practical, and widely acceptable diagnostic tool exists. In this study, 26 children with ASD (ASD+), aged 3-5 years, and 26 sex and age-matched controls are studied to investigate the diagnostic potential of the Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy. The urine FTIR spectrum results show a downward trend in the 3000-2600/cm region for ASD+ children when compared to the typically developing (TD) children of the same age. The average area of this region is 25% less in ASD+ level 3 children, 29% less in ASD+ level 2 children, and 16% less in ASD+ level 1 children compared to that of the TD children. Principal component analysis was applied to the two groups using the entire spectrum window and five peaks were identified for further analysis. The correlation between the peaks and natural urine components is validated by artificial urine solutions. Less-than-normal levels of uric acid, phosphate groups, and ammonium ([Formula: see text]) can be listed as probable causes. This study shows that ATR-FTIR can serve as a practical and non-invasive method to screen ASD using the high-frequency region of the urine spectrum.

GL7 ligand expression defines a novel subset of CD4+ TRM cells in lungs recovered from pneumococcus.

Streptococcus pneumoniae is the most common etiology of bacterial pneumonia, one of the leading causes of death in children and the elderly worldwide. During non-lethal infections with S. pneumoniae, lymphocytes accumulate in the lungs and protect against reinfection with serotype-mismatched strains. Cluster of differentiation CD4+ resident memory T (TRM) cells are known to be crucial for this protection, but the diversity of lung CD4+ TRM cells has yet to be fully delineated. We aimed to identify unique subsets and their contributions to lung immunity. After recovery from pneumococcal infections, we identified a distinct subset of CD4+ T cells defined by the phenotype CD11ahiCD69+GL7+ in mouse lungs. Phenotypic analyses for markers of lymphocyte memory and residence demonstrated that GL7+ T cells are a subset of CD4+ TRM cells. Functional studies revealed that unlike GL7- TRM subsets that were mostly (RAR-related Orphan Receptor gamma T) RORγT+, GL7+ TRM cells exhibited higher levels of (T-box expressed in T cells) T-bet and Gata-3, corresponding with increased synthesis of interferon-γ, interleukin-13, and interleukin-5, inherent to both T helper 1 (TH1) and TH2 functions. Thus, we propose that these cells provide novel contributions during pneumococcal pneumonia, serving as important determinants of lung immunity.

Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs.

Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease ( ILD ) that is recapitulated in mice expressing the STING V154M mutation ( VM ). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in ( CKI ) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders. Summary: Patients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.

Innate immune responses in pneumonia.

The lungs are an immunologically unique environment; they are exposed to innumerable pathogens and particulate matter daily. Appropriate clearance of pathogens and response to pollutants is required to prevent overwhelming infection, while preventing tissue damage and maintaining efficient gas exchange. Broadly, the innate immune system is the collection of immediate, intrinsic immune responses to pathogen or tissue injury. In this review, we will examine the innate immune responses of the lung, with a particular focus on their role in pneumonia. We will discuss the anatomic barriers and antimicrobial proteins of the lung, pathogen and injury recognition, and the role of leukocytes (macrophages, neutrophils, and innate lymphocytes) and lung stromal cells in innate immunity. Throughout the review, we will focus on new findings in innate immunity as well as features that are unique to the lung.

Urinalysis of individuals with renal hyperfiltration using ATR-FTIR spectroscopy.

Abnormal increased glomerular filtration rate (GFR), otherwise known as renal hyperfiltration (RHf), is associated with an increased risk of chronic kidney disease and cardiovascular mortality. Although it is not considered as a disease alone in medicine today, early detection of RHf is essential to reducing risk in a timely manner. However, detecting RHf is a challenge since it does not have a practical biochemical marker that can be followed or quantified. In this study, we tested the ability of ATR-FTIR spectroscopy to distinguish 17 individuals with RHf (hyperfiltraters; RHf (+)), from 20 who have normal GFR (normofiltraters; RHf(-)), using urine samples. Spectra collected from hyperfiltraters were significantly different from the control group at positions 1621, 1390, 1346, 933 and 783/cm. Intensity changes at these positions could be followed directly from the absorbance spectra without the need for pre-processing. They were tentatively attributed to urea, citrate, creatinine, phosphate groups, and uric acid, respectively. Using principal component analysis (PCA), major peaks of the second derivative forms for the classification of two groups were determined. Peaks at 1540, 1492, 1390, 1200, 1000 and 840/cm were significantly different between the two groups. Statistical analysis showed that the spectra of normofiltraters are similar; however, those of hyperfiltraters show diversity at multiple positions that can be observed both from the absorbance spectra and the second derivative profiles. This observation implies that RHf can simultaneously affect the excretion of many substances, and that a spectroscopic analysis of urine can be used as a rapid and non-invasive pre-screening tool.

Lectin-like oxidized low-density lipoprotein receptor 1 attenuates pneumonia-induced lung injury.

Identifying host factors that contribute to pneumonia incidence and severity are of utmost importance to guiding the development of more effective therapies. Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1, encoded by OLR1) is a scavenger receptor known to promote vascular injury and inflammation, but whether and how LOX-1 functions in the lung are unknown. Here, we provide evidence of substantial accumulation of LOX-1 in the lungs of patients with acute respiratory distress syndrome and in mice with pneumonia. Unlike previously described injurious contributions of LOX-1, we found that LOX-1 is uniquely protective in the pulmonary airspaces, limiting proteinaceous edema and inflammation. We also identified alveolar macrophages and recruited neutrophils as 2 prominent sites of LOX-1 expression in the lungs, whereby macrophages are capable of further induction during pneumonia and neutrophils exhibit a rapid, but heterogenous, elevation of LOX-1 in the infected lung. Blockade of LOX-1 led to dysregulated immune signaling in alveolar macrophages, marked by alterations in activation markers and a concomitant elevation of inflammatory gene networks. However, bone marrow chimeras also suggested a prominent role for neutrophils in LOX-1-mediated lung protection, further supported by LOX-1+ neutrophils exhibiting transcriptional changes consistent with reparative processes. Taken together, this work establishes LOX-1 as a tissue-protective factor in the lungs during pneumonia, possibly mediated by its influence on immune signaling in alveolar macrophages and LOX-1+ airspace neutrophils.

Investigations of pH-dependent dynamic properties of OmpG-16SL, an outer membrane protein G mutant by ATR-FTIR spectroscopy.

In this paper, the dynamic properties of outer membrane protein G mutant (OmpG-16SL) are investigated with ATR-FTIR spectroscopy. While OmpG-WT has 14 ß-strands in its structure, the mutant is designed to have 16 ß-strands with the intention of creating an enlarged pore. Loop L6 is elongated by introducing six residues, two of which are negatively charged. The solvent accessibility of the OmpG-16SL mutant is compared with WT and a previously reported mutant OmpG-16S by tracking the 1H/2H exchange kinetics in acidic and neutral buffer conditions. The exchange kinetics and dynamics in the fast and slow exchange phases are separately investigated using the 2DCOS technique, which enables the tracking of the structural changes at each phase of the exchange process. The results suggest that the mutant OmpG-16SL is equally exposed to buffer in both acidic and neutral pH conditions. Additionally, the time range in the fast phase is very short - one-tenth of that for WT - and most of the exchange is completed in this phase. This fast exchange within minutes is also indicative of the presence of highly flexible and/or unstructured regions. In all, the fast exchange rates independent of the buffer pH justify the assumption that there is an altered interaction among the charged residues, which leads to a steadily-open pore. The role of the side-chain interactions within the pore and between the loops involving the loop L6 is also discussed.

Recruitment and training of alveolar macrophages after pneumococcal pneumonia.

Recovery from pneumococcal pneumonia remodels the pool of alveolar macrophages so that they exhibit new surface marker profiles, transcriptomes, metabolomes, and responses to infection. Mechanisms mediating alveolar macrophage phenotypes after pneumococcal pneumonia have not been delineated. IFN-γ and its receptor on alveolar macrophages were essential for certain, but not all, aspects of the remodeled alveolar macrophage phenotype. IFN-γ was produced by CD4+ T cells plus other cells, and CD4+ cell depletion did not prevent alveolar macrophage remodeling. In mice infected or recovering from pneumococcus, monocytes were recruited to the lungs, and the monocyte-derived macrophages developed characteristics of alveolar macrophages. CCR2 mediated the early monocyte recruitment but was not essential to the development of the remodeled alveolar macrophage phenotype. Lineage tracing demonstrated that recovery from pneumococcal pneumonias converted the pool of alveolar macrophages from being primarily of embryonic origin to being primarily of adult hematopoietic stem cell origin. Alveolar macrophages of either origin demonstrated similar remodeled phenotypes, suggesting that ontogeny did not dictate phenotype. Our data reveal that the remodeled alveolar macrophage phenotype in lungs recovered from pneumococcal pneumonia results from a combination of new recruitment plus training of both the original cells and the new recruits.

Epithelial LIF signaling limits apoptosis and lung injury during bacterial pneumonia.

During bacterial pneumonia, alveolar epithelial cells are critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. Although LIFR is expressed on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing Lifr, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of Lifr. Sequencing data indicated that ATII cells were significantly impacted by pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.

Antigen presentation by lung epithelial cells directs CD4+ TRM cell function and regulates barrier immunity.

Barrier tissues are populated by functionally plastic CD4+ resident memory T (TRM) cells. Whether the barrier epithelium regulates CD4+ TRM cell locations, plasticity and activities remains unclear. Here we report that lung epithelial cells, including distinct surfactant protein C (SPC)lowMHChigh epithelial cells, function as anatomically-segregated and temporally-dynamic antigen presenting cells. In vivo ablation of lung epithelial MHC-II results in altered localization of CD4+ TRM cells. Recurrent encounters with cognate antigen in the absence of epithelial MHC-II leads CD4+ TRM cells to co-express several classically antagonistic lineage-defining transcription factors, changes their cytokine profiles, and results in dysregulated barrier immunity. In addition, lung epithelial MHC-II is needed for surface expression of PD-L1, which engages its ligand PD-1 to constrain lung CD4+ TRM cell phenotypes. Thus, we establish epithelial antigen presentation as a critical regulator of CD4+ TRM cell function and identify epithelial-CD4+ TRM cell immune interactions as core elements of barrier immunity.

Liver-Dependent Lung Remodeling during Systemic Inflammation Shapes Responses to Secondary Infection.

Systemic duress, such as that elicited by sepsis, burns, or trauma, predisposes patients to secondary pneumonia, demanding better understanding of host pathways influencing this deleterious connection. These pre-existing circumstances are capable of triggering the hepatic acute-phase response (APR), which we previously demonstrated is essential for limiting susceptibility to secondary lung infections. To identify potential mechanisms underlying protection afforded by the lung-liver axis, our studies aimed to evaluate liver-dependent lung reprogramming when a systemic inflammatory challenge precedes pneumonia. Wild-type mice and APR-deficient littermate mice with hepatocyte-specific deletion of STAT3 (hepSTAT3-/-), a transcription factor necessary for full APR initiation, were challenged i.p. with LPS to induce endotoxemia. After 18 h, pneumonia was induced by intratracheal Escherichia coli instillation. Endotoxemia elicited significant transcriptional alterations in the lungs of wild-type and hepSTAT3-/- mice, with nearly 2000 differentially expressed genes between genotypes. The gene signatures revealed exaggerated immune activity in the lungs of hepSTAT3-/- mice, which were compromised in their capacity to launch additional cytokine responses to secondary infection. Proteomics revealed substantial liver-dependent modifications in the airspaces of pneumonic mice, implicating a network of dispatched liver-derived mediators influencing lung homeostasis. These results indicate that after systemic inflammation, liver acute-phase changes dramatically remodel the lungs, resulting in a modified landscape for any stimuli encountered thereafter. Based on the established vulnerability of hepSTAT3-/- mice to secondary lung infections, we believe that intact liver function is critical for maintaining the immunological responsiveness of the lungs.

Novel ELISA Protocol Links Pre-Existing SARS-CoV-2 Reactive Antibodies With Endemic Coronavirus Immunity and Age and Reveals Improved Serologic Identification of Acute COVID-19 via Multi-Parameter Detection.

The COVID-19 pandemic has drastically impacted work, economy, and way of life. Sensitive measurement of SARS-CoV-2 specific antibodies would provide new insight into pre-existing immunity, virus transmission dynamics, and the nuances of SARS-CoV-2 pathogenesis. To date, existing SARS-CoV-2 serology tests have limited utility due to insufficient reliable detection of antibody levels lower than what is typically present after several days of symptoms. To measure lower quantities of SARS-CoV-2 IgM, IgG, and IgA with higher resolution than existing assays, we developed a new ELISA protocol with a distinct plate washing procedure and timed plate development via use of a standard curve. Very low optical densities from samples added to buffer coated wells at as low as a 1:5 dilution are reported using this 'BU ELISA' method. Use of this method revealed circulating SARS-CoV-2 receptor binding domain (RBD) and nucleocapsid protein (N) reactive antibodies (IgG, IgM, and/or IgA) in 44 and 100 percent of pre-pandemic subjects, respectively, and the magnitude of these antibodies tracked with antibody levels of analogous viral proteins from endemic coronavirus (eCoV) strains. The disease status (HIV, SLE) of unexposed subjects was not linked with SARS-CoV-2 reactive antibody levels; however, quantities were significantly lower in subjects over 70 years of age compared with younger counterparts. Also, we measured SARS-CoV-2 RBD- and N- specific IgM, IgG, and IgA antibodies from 29 SARS-CoV-2 infected individuals at varying disease states, including 10 acute COVID-19 hospitalized subjects with negative serology results by the EUA approved Abbott IgG chemiluminescent microparticle immunoassay. Measurements of SARS-CoV-2 RBD- and N- specific IgM, IgG, IgA levels measured by the BU ELISA revealed higher signal from 9 of the 10 Abbott test negative COVID-19 subjects than all pre-pandemic samples for at least one antibody specificity/isotype, implicating improved serologic identification of SARS-CoV-2 infection via multi-parameter, high sensitive antibody detection. We propose that this improved ELISA protocol, which is straightforward to perform, low cost, and uses readily available commercial reagents, is a useful tool to elucidate new information about SARS-CoV-2 infection and immunity and has promising implications for improved detection of all analytes measurable by this platform.

Urine analysis using FTIR spectroscopy: A study on healthy adults and children.

Urine spectra from 108 healthy volunteers are studied by attenuated total refraction-Fourier transform infrared (ATR-FTIR) spectroscopy. The spectral features are correlated with observable urine components. The variation of spectra within a healthy population is quantified and a library of reference spectra is constructed. Using the band assignments, these spectra are compared with both age-wise and gender-wise. Children show the least intensity variations compared to both adult groups. Young adults show the highest variation, particularly in the 1650 to 1400 cm-1 and 1200 to 900 cm-1 regions. These results indicate the importance of the size of the control group in comparative studies utilizing FTIR. Age-wise comparisons reveal that phosphate and sulfate excretion decreases with age, and that the variance of phosphate among individuals is higher with adults. As for gender-wise comparisons, females show a slightly higher citrate content at 1390 cm-1 regardless of the age and they show a higher variance in the 1200 to 1000 cm-1 region when compared to men.

Structural properties of an engineered outer membrane protein G mutant, OmpG-16SL, investigated with infrared spectroscopy.

The structural and functional differences between wild type (WT) outer membrane protein G and its two mutants are investigated with Fourier transform infrared spectroscopy. Both mutants have a long extension to the primary sequence to increase the number of ß-strands from 14 (wild type) to 16 in an attempt to enlarge the pore diameter. The comparison among proteins is made in terms of pH-dependent conformational changes and thermal stability. Results show that all proteins respond to pH change but at different degrees. At acidic environment, all proteins contain the same number of residues participated in ß-sheet structure. However, at neutral pH, the mutants have less ordered structure compared to WT porin. Thermal stability tests show that mutants differ significantly from WT porin at neutral pH. Although the transition temperature is directly proportional with the amount of ß-sheet content, the changes in the pre-transition phase that pave the way to structural breakdown are shown to involve interactions among charged residues by two-dimensional correlation spectroscopy analysis. Results of the analysis show that side chain interactions play an active role under increasing temperature. Both mutants have more unordered secondary structure but they respond to pH change in tertiary structure level. Findings of this study provided deeper insight on the active players in structural stability of the WT porin.Communicated by Ramaswamy H. Sarma [Formula: see text].

A New Artificial Urine Protocol to Better Imitate Human Urine.

Artificial urine has many advantages over human urine for research and educational purposes. By closely mimicking healthy individuals' urine, it may also be important in discovering novel biomarkers. However, up until now, there has not been any specific protocol to prove the similarity in terms of the chemical composition at the molecular level. In this study, a new artificial urine protocol is established to mimics the urine of healthy individuals. The multi-purpose artificial urine (MP-AU) presented here is compared with two other protocols most cited in literature. Furthermore, these three protocols are also compared with samples from 28 healthy young individuals. To do so, attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR) is used, according to which MP-AU shows a significantly close similarity with human urine. In formulating MP-AU, the infrared spectra of nine compounds is provided, making possible the band assignment of some absorption bands to certain compounds. Given its properties, the MP-AU protocol introduced here is both economical and practical, making it useful when designing comparative-controlled experiments.

Roles of interleukin-11 during acute bacterial pneumonia.

Interleukin-11 (IL-11) is an interleukin-6 (IL-6) family cytokine shown to play a protective role in acute inflammatory settings including systemic infection. In this study we addressed the role of IL-11 in acute bacterial pneumonia using a mouse model of E. coli pneumonia. Compared with other related cytokines, IL-11 protein was maintained at high levels in the lung at baseline, with only mild alterations in whole lung and BALF levels during acute infection. The primary source of IL-11 in the lung was the epithelium, but steady state production was not dependent on the inflammatory transcription factor nuclear factor kappa B in cells of either myeloid or epithelial lineage. Blockade of IL-11 with neutralizing antibodies resulted in a mild but significant decrease in neutrophil recruitment and increase in pulmonary edema during pneumonia, without detectable alterations in bacterial clearance. Exogenous IL-11 administration, however, had no effect at baseline or during infection. Overall, we conclude that maintenance of lung IL-11 concentrations may influence acute pulmonary inflammation during infection, albeit modestly.

NF-κB RelA Is Required for Hepatoprotection during Pneumonia and Sepsis.

Pneumonia and sepsis are distinct but integrally linked public health concerns. The hepatic acute-phase response (APR), which is largely dependent on transcription factors NF-κB RelA and STAT3, is a hallmark of these pathologies and other injurious conditions. Inactivation of the APR can promote liver injury, a frequently observed organ dysfunction during sepsis. However, whether or how the acute-phase changes promote liver tissue resilience during infections is unclear. To determine the hepatoprotective role of the hepatic APR, we utilized mice bearing hepatocyte-specific deletions of either RelA or STAT3. Mice were challenged intratracheally (i.t.), intravenously (i.v.), or intraperitoneally (i.p.) with Escherichia coli, Klebsiella pneumoniae, Streptococcus pneumoniae, lipopolysaccharide (LPS), or alpha-galactosylceramide (αGalCer) to induce pneumonia, sepsis, or NKT cell activation. Liver injury was observed in RelA-null (hepRelAΔ/Δ) mice but not STAT3-null (hepSTAT3Δ/Δ) mice during pneumonia. The absence of RelA resulted in hepatotoxicity across several models of pneumonia, sepsis, and NKT cell activation. Injury was associated with increased levels of activated caspase-3 and -8 and substantial alteration of the hepatic transcriptome. Hepatotoxicity in the absence of RelA could be reversed by neutralization of tumor necrosis factor alpha (TNF-α). These results indicate the requirement of RelA-dependent inducible hepatoprotection during pneumonia and sepsis. Further, the results demonstrate that RelA-dependent gene programs are critical for maintaining liver homeostasis against TNF-α-driven immunotoxicity.