Safety of proteasome inhibitor drugs for the treatment of multiple myeloma post-marketing: a pharmacovigilance investigation based on the FDA adverse event reporting system.

BACKGROUND: The use of proteasome inhibitors (PIs), namely Bortezomib and Carfilzomib, revolutionized multiple myeloma (MM) treatment. Understanding their distinct adverse event (AE) profiles aids in tailored treatment plans. RESEARCH DESIGN AND METHODS: We analyzed FDA Adverse Event Reporting System (FAERS) data (Q1 2012-Q4 2023) for Bortezomib and Carfilzomib, utilizing reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN). RESULTS: FAERS yielded 19,720 Bortezomib and 12,252 Carfilzomib AE reports. Males aged 45-65 exhibited higher AE susceptibility. Common AE systems included Infections, Nervous System Disorders, Blood Disorders, General Disorders, Cardiac Disorders, and Renal Disorders. New Bortezomib signals were sepsis and colitis. Carfilzomib exhibited elevated cardiac and renal toxicity but reduced peripheral neuropathy and thrombocytopenia. CONCLUSIONS: FAERS analysis revealed new AE signals (sepsis, colitis) for Bortezomib and highlighted Carfilzomib's heightened cardiac and renal risks compared to Bortezomib. Balancing PIs' benefits and risks is crucial for clinical decision-making.

Tumor lymphangiogenesis index reveals the immune landscape and immunotherapy response in lung adenocarcinoma.

Background: Lymphangiogenesis (LYM) has an important role in tumor progression and is strongly associated with tumor metastasis. However, the clinical application of LYM has not progressed as expected. The potential value of LYM needs to be further developed in lung adenocarcinoma (LUAD) patients. Methods: The Sequencing data and clinical characteristics of LUAD patients were downloaded from The Cancer Genome Atlas and GEO databases. Multiple machine learning algorithms were used to screen feature genes and develop the LYM index. Immune cell infiltration, immune checkpoint expression, Tumor Immune Dysfunction and Exclusion (TIDE) algorithm and drug sensitivity analysis were used to explore the correlation of LYM index with immune profile and anti-tumor therapy. Results: We screened four lymphangiogenic feature genes (PECAM1, TIMP1, CXCL5 and PDGFB) to construct LYM index based on multiple machine learning algorithms. We divided LUAD patients into the high LYM index group and the low LYM index group based on the median LYM index. LYM index is a risk factor for the prognosis of LUAD patients. In addition, there was a significant difference in immune profile between high LYM index and low LYM index groups. LUAD patients in the low LYM index group seemed to benefit more from immunotherapy based on the results of TIDE algorithm. Conclusion: Overall, we confirmed that the LYM index is a prognostic risk factor and a valuable predictor of immunotherapy response in LUAD patients, which provides new evidence for the potential application of LYM.

The prognostic evaluation of ALBI score in endoscopic treatment of esophagogastric varices hemorrhage in liver cirrhosis.

To analyze the independent risk factors for recurrent bleeding and death within 1 year after endoscopic treatment of esophagogastric varices hemorrhage (EGVB) in patients with liver cirrhosis, and to validate the predictive value of ALBI score for recurrent bleeding and death within 1 year after endoscopic treatment of EGVB in patients with liver cirrhosis. A total of 338 patients with EGVB who received endoscopic treatment for the first time in the Department of Gastroenterology, First Affiliated Hospital of Nanchang University from January 1, 2016 to March 1, 2020 were selected. A database was established to analyze the patients' demographic data, surgical variables and postoperative outcomes. All patients were contacted and followed up to verify the predictive value of ALBI score for recurrent bleeding and mortality. 130 patients had rebleeding within 1 year after surgery (38.5%). 66 patients died within 1 year after surgery (19.5%). Patients with ALBI grade 3 had significantly higher rebleeding and mortality rates than those with grades 1 and 2. The AUC was used to compare the predictive value of the four scores for rebleeding and mortality within one year after endoscopic surgery. Both ALBI scores had the largest AUC. The ALBI score has certain predictive value for rebleeding and mortality within 1 year after endoscopic therapy in patients with cirrhotic EGVB.

Dendritic cell-based vaccine prepared with recombinant Lactococcus lactis enhances antigen cross-presentation and antitumor efficacy through ROS production.

Introduction: Lactococcus lactis (L.L) is safe and can be used as vehicle. In this study, the immunoregulatory effect of L.L on dendritic cell (DC) activation and mechanism were investigated. The immune responses and antigen cross-presentation mechanism of DC-based vaccine prepared with OVA recombinant L.L were explored. Methods: Confocal microscopy and flow cytometry were used to analyze the mechanism of L.L promoting DC maturation, phagosome membrane rupture and antigen presentation. The antitumor effect of DC vaccine prepared with L.L-OVA was assessed in the B16-OVA tumor mouse model. Results: L.L significantly promoted DC maturation, which was partially dependent on TLR2 and downstream MAPK and NF-κB signaling pathways. L.L was internalized into DCs by endocytosis and did not co-localized with lysosome. OVA recombinant L.L enhanced antigen cross-presentation of DCs through the phagosome-to-cytosol pathway in a reactive oxygen species (ROS)- and proteasome-dependent manner. In mouse experiments, L.L increased the migration of DCs to draining lymph node and DC vaccine prepared with OVA recombinant L.L induced strong antigen-specific Th1 and cytotoxic T lymphocyte responses, which significantly inhibited B16-OVA tumor growth. Conclusion: This study demonstrated that recombinant L.L as an antigen delivery system prepared DC vaccine can enhance the antigen cross-presentation and antitumor efficacy.

The Role of Innate Immune Cells in Cardiac Injury and Repair: A Metabolic Perspective.

PURPOSE OF REVIEW: Recent technological advances have identified distinct subpopulations and roles of the cardiac innate immune cells, specifically macrophages and neutrophils. Studies on distinct metabolic pathways of macrophage and neutrophil in cardiac injury are expanding. Here, we elaborate on the roles of cardiac macrophages and neutrophils in concomitance with their metabolism in normal and diseased hearts. RECENT FINDINGS: Single-cell techniques combined with fate mapping have identified the clusters of innate immune cell subpopulations present in the resting and diseased hearts. We are beginning to know about the presence of cardiac resident macrophages and their functions. Resident macrophages perform cardiac homeostatic roles, whereas infiltrating neutrophils and macrophages contribute to tissue damage during cardiac injury with eventual role in repair. Prior studies show that metabolic pathways regulate the phenotypes of the macrophages and neutrophils during cardiac injury. Profiling the metabolism of the innate immune cells, especially of resident macrophages during chronic and acute cardiac diseases, can further the understanding of cardiac immunometabolism.

Primary papillary epithelial tumor of the sella and posterior pituitary tumor show similar (epi)genetic features and constitute a single neuro-oncological entity.

BACKGROUND: "Primary papillary epithelial tumor of the sella (PPETS)" is a recently described rare tumor entity of the central nervous system (CNS) with stereotypic location in the sella. Comprehensive molecular investigations and epigenetic profiles of PPETS have not been performed to date. METHODS: We report a comprehensive clinical, histopathologic, and molecular assessment of 5 PPETS cases in comparison with a cohort composed of 7 choroid plexus papilloma (CPP), 7 central neurocytoma (CN), 15 posterior pituitary tumor (PPT) including 4 pituicytoma, 6 granular cell tumors of the sellar region (GCT), and 5 spindle cell oncocytoma. RESULTS: All PPETS had good outcomes. Immunohistochemically, PPETS tumors showed positive staining with TTF1, EMA, AE1/AE3, MAP2, and Vimentin, but were negatively stained with Syn, GFAP, CgA, and S100, and sporadically stained with Ki-67. In unsupervised hierarchical clustering and t-distributed stochastic neighbor embedding analyses of DNA-methylation data, PPETS and PPT tumors formed a distinct cluster irrespective of their histologic types. However, PPETS tumors did not cluster together with CPP and CN samples. Similar findings were obtained when our samples were projected into the reference cohort of the brain tumor classifier. Substantial fractions of the PPETS and PPT tumors shared broadly similar chromosomal copy number alterations. No mutations were detected using targeted next-generation sequencing. CONCLUSIONS: Though more cases are needed to further elucidate the molecular pathogenesis of these tumors, our findings indicate that PPETS and PPT tumors may constitute a single neurooncological entity.

Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction.

Innate immune cells play important roles in tissue injury and repair following acute myocardial infarction (MI). Although reprogramming of macrophage metabolism has been observed during inflammation and resolution phases, the mechanistic link to macrophage phenotype is not fully understood. In this study, we found that myeloid-specific deletion (mKO) of mitochondrial complex I protein, encoded by Ndufs4, reproduced the proinflammatory metabolic profile in macrophages and exaggerated the response to LPS. Moreover, mKO mice showed increased mortality, poor scar formation, and worsened cardiac function 30 days after MI. We observed a greater inflammatory response in mKO mice on day 1 followed by increased cell death of infiltrating macrophages and blunted transition to the reparative phase during post-MI days 3-7. Efferocytosis was impaired in mKO macrophages, leading to lower expression of antiinflammatory cytokines and tissue repair factors, which suppressed the proliferation and activation of myofibroblasts in the infarcted area. Mitochondria-targeted ROS scavenging rescued these impairments, improved myofibroblast function in vivo, and reduced post-MI mortality in mKO mice. Together these results reveal a critical role of mitochondria in inflammation resolution and tissue repair via modulation of efferocytosis and crosstalk with fibroblasts. These findings have potential significance for post-MI recovery as well as for other inflammatory conditions.

Evaluation and mechanism of immune enhancement effects of Pleurotus ferulae polysaccharides-gold nanoparticles.

We previously demonstrated that Pleurotus ferulae polysaccharide (PFPS) promoted dendritic cell (DC) maturation through the TLR4 signaling pathway. To improve PFPS activity and bioavailability, gold nanoparticles with PFPS (PFPS-Au NPs) were synthesized. Of note, although the polysaccharide content of PFPS-Au NPs was only one tenth of PFPS, PFPS-Au NPs enhanced the immunostimulatory activities of PFPS in the maturation and function of dendritic cells (DCs) by TLR4 and NLRP3 signaling pathways, evidenced by stronger activation of the down-stream MAPK and NF-κB pathways and NLRP3 inflammasome pathway. More importantly, PFPS-Au NPs enhanced DC migration and murine immunity, particularly in type 1 T-helper cell responses. Moreover, the half-life of PFPS-Au NPs (2.217 ± 0.187 h) was longer than that of PFPS (1.39 ± 0.257 h) in the blood and the distribution of PFPS-Au NPs (19.8 %) in the spleen was significantly increased compared with PFPS (13.3 %), indicating the improved bioavailability in vivo. PFPS-Au NPs as an adjuvant promoted antigen-specific cellular immune responses to an HPV DC-based vaccine, which significantly inhibited the growth of TC-1 tumors in mice. All results suggest that the prepared Au NPs could enhance PFPS-immunostimulatory activity, which will pave the way for PFPS-Au NPs to be applied in clinical trials.

Development and Validation of Ferroptosis-Related lncRNAs as Prognosis and Diagnosis Biomarkers for Breast Cancer.

Breast cancer (BC) is one of the most common malignancies affecting women. Ferroptosis is a novel cancer treatment option. The present study is aimed to identify suitable ferroptosis-related lncRNAs to predict and diagnose BC. Differential expression and Cox regression analyses were used to screen suitable prognostic biomarkers and construct a suitable risk model. We identified four ferroptosis-related differentially expressed lncRNAs (FR-DELs) (LINC01152, AC004585.1, MAPT-IT1, and AC026401.3), which were independently correlated with the overall survival of BC patients. The area under the curve value of the prognostic model using those four biomarkers was over 0.60 in all three groups. The sensitivity and specificity of the diagnostic model using those four biomarkers were 86.89% and 86.73%, respectively. Our present study indicated that these four FR-DELs (LINC01152, AC004585.1, MAPT-IT1, and AC026401.3) could be prognostic biomarkers for BC, although clinical validation studies are required.

In Vitro and In Vivo Dendritic Cell Immune Stimulation Effect of Low Molecular Weight Fucoidan from New Zealand Undaria pinnatifida.

Low molecular weight fucoidan (LMWF) has been reported to have immunomodulation effects through the increase of the activation and function of macrophages. In this study, the regulating effect of LMWF from Undaria pinnatifida grown in New Zealand on dendritic cells (DCs) was investigated. We discovered that LMWF could stimulate DCs' maturation and migration, as well as CD4+ and CD8+ T cells' proliferation in vitro. We proved that this immune promoting activity is activated through TLR4 and its downstream MAPK and NF-κB signaling pathways. Further in vivo (mouse model) investigation showed that LMWF has a strong immunological boosting effect, such as facilitating the proliferation of immune cells and increasing the index of immune organs. These findings suggest that LMWF has a positive immunomodulatory effect and is a promising candidate to supplement cancer immunotherapy.

Host Defense against Klebsiella pneumoniae Pneumonia Is Augmented by Lung-Derived Mesenchymal Stem Cells.

Klebsiella pneumoniae is a common cause of Gram-negative pneumonia. The spread of antibiotic-resistant and hypervirulent strains has made treatment more challenging. This study sought to determine the immunomodulatory, antibacterial, and therapeutic potential of purified murine stem cell Ag-1+ (Sca-1+) lung mesenchymal stem cells (LMSCs) using in vitro cell culture and an in vivo mouse model of pneumonia caused by K pneumoniae. Sca-1+ LMSCs are plastic adherent, possess colony-forming capacity, express mesenchymal stem cell markers, differentiate into osteogenic and adipogenic lineages in vitro, and exhibit a high proliferative capacity. Further, these Sca-1+ LMSCs are morphologically similar to fibroblasts but differ ultrastructurally. Moreover, Sca-1+ LMSCs have the capacity to inhibit LPS-induced secretion of inflammatory cytokines by bone marrow-derived macrophages and neutrophils in vitro. Sca-1+ LMSCs inhibit the growth of K pneumoniae more potently than do neutrophils. Sca-1+ LMSCs also possess the intrinsic ability to phagocytize and kill K. pneumoniae intracellularly. Whereas the induction of autophagy promotes bacterial replication, inhibition of autophagy enhances the intracellular clearance of K. pneumoniae in Sca-1+ LMSCs during the early time of infection. Adoptive transfer of Sca-1+ LMSCs in K. pneumoniae-infected mice improved survival, reduced inflammatory cells in bronchoalveolar lavage fluid, reduced inflammatory cytokine levels and pathological lesions in the lung, and enhanced bacterial clearance in the lung and in extrapulmonary organs. To our knowledge, these results together illustrate for the first time the protective role of LMSCs in bacterial pneumonia.

NLRP6 modulates neutrophil homeostasis in bacterial pneumonia-derived sepsis.

Bacterial pneumonia is a significant cause of morbidity, mortality, and health care expenditures. Optimum neutrophil recruitment and their function are critical defense mechanisms against respiratory pathogens. The nucleotide-binding oligomerization domain-like receptor (NLRP) 6 controls gut microbiota and immune response to systemic and enteric infections. However, the importance of NLRP6 in neutrophil homeostasis following lung infection remains elusive. To investigate the role of NLRs in neutrophil homeostasis, we used Nlrp6 gene-deficient (Nlrp6-/-) mice in a model of Klebsiella pneumoniae-induced pneumonia-derived sepsis. We demonstrated that NLRP6 is critical for host survival, bacterial clearance, neutrophil influx, and CXC-chemokine production. Kp-infected Nlrp6-/- mice have reduced numbers of hematopoietic stem cells and granulocyte-monocyte progenitors but increased retention of matured neutrophils in bone marrow. Neutrophil extracellular trap (NET) formation and NET-mediated bacterial killing were also impaired in Nlrp6-/- neutrophils in vitro. Furthermore, recombinant CXCL1 rescued the impaired host defense, granulopoietic response, and NETosis in Kp-infected Nlrp6-/- mice. Using A/J background mice and co-housing experiments, our findings revealed that the susceptible phenotype of Nlrp6-/- mice is not strain-specific and gut microbiota-dependent. Taken together, these data unveil NLRP6 as a central regulator of neutrophil recruitment, generation, and function during bacterial pneumonia followed by sepsis.

Impact of Hepatic Steatosis on the Antiviral Effects of PEG-IFNα-2a in Patients with Chronic Hepatitis B and the Associated Mechanism.

OBJECTIVE: To investigate the risk factors for hepatic steatosis in chronic hepatitis B (CHB), to determine its correlation with liver necroinflammation and fibrosis and response to peginterferon alpha-2a (PEG-IFNα-2a) antiviral therapy, and to explore the mechanisms underlying the poor antiviral effect of PEG-IFNα-2a in CHB patients with hepatic steatosis. METHODS: We analysed the impact of hepatic steatosis on the antiviral effect of PEG-IFNα-2a on CHB patients in a cohort of 226 patients who underwent pretherapeutic liver biopsy. To assess the complete response (CR), virological response (VR), and biochemical response (BR), the 226 patients were treated with PEG-IFNα-2a for 48 weeks and were followed-up for 24 weeks. The expressions of hepatitis B surface antigen (HBsAg) and hepatitis B core antigen (HBcAg) in the liver tissue were detected in all patients to explore the possible mechanism of hepatic steatosis with regard to antiviral effects. RESULTS: The patients were divided into four groups based on the severity of hepatic steatosis: 119 with no steatosis, 76 with mild steatosis, 22 with moderate steatosis, and 9 with severe steatosis. In the hepatic steatosis groups, the proportions of male patients, patients aged >40 years, patients with hyperuricaemia, patients with a BMI > 23 kg/m2, and total cholesterol (TC), triglyceride (TG), glucose (GLU), and uric acid (UA) levels were significantly higher than those in the group without steatosis, whereas the alanine aminotransferase (ALT) and aspartate transaminase (AST) levels were significantly lower than those in the group without steatosis. The multivariate analysis results indicated that a BMI > 23 kg/m2 was independently associated with CHB patients with hepatic steatosis; the levels of baseline AST and UA were independently associated with CHB patients with significant hepatic steatosis, and the baseline AST level was independently associated with significant liver fibrosis. After 48 weeks of treatment and 24 weeks of follow-up, the rates of CR, VR, and BR had gradually decreased, whereas the severity of hepatic steatosis had increased. CONCLUSION: Hepatic steatosis can reduce the efficacy of PEG-IFNα-2a in the treatment of CHB patients, and its mechanism may be related to the different HBcAg expression patterns in liver tissue.

The immunostimulatory activity of polysaccharides from Glycyrrhiza uralensis.

BACKGROUND: The enhancement of immunity is very important for immunocompromised patients such as cancer patients with radiotherapy or chemotherapy. Glycyrrhiza uralensis has been used as food and medicine for a long history. G. uralensis polysaccharides (GUPS) were prepared and its immunostimulatory effects were investigated. METHODS: Human monocyte-derived dendritic cells (DCs) and murine bone marrow-derived DCs were treated with different concentrations of GUPS. The DCs maturation and cytokine production were analyzed by flow cytometry and ELISA, respectively. Inhibitors and Western blot were used to study the mechanism of GUPS. The immunostimulatory effects of GUPS were further evaluated by naïve mouse model and immunosuppressive mouse model induced by cyclophosphamide. RESULTS: GUPS significantly promoted the maturation and cytokine secretion of human monocyte-derived DCs and murine bone marrow-derived DCs through TLR4 and down-stream p38, JNK and NF-κB signaling pathways. Interestingly, the migration of GUPS treated-DCs to lymph node was increased. In the mouse model, GUPS increased IL-12 production in sera but not for TNF-α. Moreover, GUPS ameliorated the side effect of cyclophosphamide and improved the immunity of immunosuppressive mice induced by cyclophosphamide. These results suggested that GUPS might be used for cancer therapy to ameliorate the side effect of chemotherapy and enhance the immunity.

Preparation, Characterization, and Immuno-Enhancing Activity of Polysaccharides from Glycyrrhiza uralensis.

Glycyrrhiza uralensis is a Chinese herbal medicine with various bioactivities. Three fractions (GUPS-I, GUPS-II and GUPS-III) of G. uralensis polysaccharides (GUPS) were obtained with molecular weights of 1.06, 29.1, and 14.9 kDa, respectively. The monosaccharide compositions of GUPS-II and GUPS-III were similar, while that of GUPS-I was distinctively different. The results of scanning electron microscopy, FT-IR, and NMR suggested that GUPS-II and GUPS-III were flaky with a smooth surface and contained α- and ß-glycosidic linkages, while GUPS-I was granulated and contained only α-glycosidic linkages. Moreover, GUPS-II and GUPS-III exhibited better bioactivities on the maturation and cytokine production of dendritic cells (DCs) in vitro than that of GUPS-I. An in vivo experiment showed that only GUPS-II significantly enhanced the maturation of DCs. These results indicate that GUPS-II has the potential to be used in combination with cancer immunotherapy to enhance the therapeutic effect.

Rapid, label-free detection of intracranial germinoma using multiphoton microscopy.

Accurate histopathological diagnosis is essential for facilitating the optimal surgical management of intracranial germinoma. Current intraoperative histological methods are time- and labor-intensive and often produce artifacts. Multiphoton microscopy (MPM) is a label-free imaging technique that can produce intraoperative histological images of fresh, unprocessed surgical specimens. We employ an MPM based on second-harmonic generation and two-photon excited fluorescence microscopy to image fresh, unfixed, and unstained human germinoma specimens. We show that label-free MPM is not only capable of identifying various cells in human germinoma tissue but also capable of revealing the characteristics of germinoma such as granuloma, stromal fibrosis, calcification, as well as the abnormal and uneven structures of blood vessels. In conjunction with custom-developed image-processing algorithms, MPM can further quantify and characterize the extent of stromal fibrosis and calcification. Our results provide insight into how MPM can deliver rapid diagnostic histological data that could inform the surgical management of intracranial germinoma.

Quantitative assessment of microenvironment characteristics and metabolic activity in glioma via multiphoton microscopy.

Tumor microenvironment and metabolic activity in gliomas are the important biomarkers to evaluate the progression of gliomas. Many evidences have suggested that the targeting of metabolic activity and tumor microenvironment simultaneously can be more effective to take the tumor therapy. Therefore, the noninvasive, accurate assessment of tumor microenvironment and metabolic activity is quite important in clinical practice. Multiphoton microscopy (MPM), based on two-photon-excited fluorescence and second harmonic generation was performed on unstained glioma tissues. With our combined image analysis approaches, our research findings indicate that MPM is able to qualitatively and quantitatively describe the microenvironment characteristics in gliomas, such as collage deposition in extracellular matrix, lymphocyte infiltration and tumor angiogenesis, etc. Meanwhile, the metabolic activity can also be quantitatively evaluated by optical redox ratio, NADH and FAD intensity. With the microendoscope and fiberscope are portable, MPM technique can be used to perform in-vivo studies and clinical examinations in gliomas.

Automatic and label-free identification of blood vessels in gliomas using the combination of multiphoton microscopy and image analysis.

Currently, the targeted treatment of tumor based on the tumor microenvironment is newly developed. Blood vessels are the key parts in the tumor microenvironment, which is taken as a new visible target for tumor therapy. Multiphoton microscopy (MPM), based on the second harmonic generation and two-photon excited fluorescence, is available to make the label-free analysis on the blood vessels in human gliomas. MPM can reveal the vascular morphological characteristics in gliomas, including vascular malformation, intense vascular proliferation, perivascular collagen deposition, perivascular lymphocytes aggregation and microvascular proliferation. In addition, the image analysis algorithms were developed to automatically calculate the perivascular collagen content, vascular cavity area, lumen area, wall area and vessel number. Thus, the vascular morphology, the perivascular collagen deposition and intense vascular proliferation degree can be further quantitatively characterized. Compared with the pathological analysis, the combination of MPM and image analysis has potential advantages in making a quantitative and qualitative analyzing on vascular morphology in glioma microenvironment. As micro-endoscope and two-photon fiberscope are technologically improved, this combined method will be a useful imaging way to make the real-time research on the targeting tumor microenvironment in gliomas.

CXCL1 regulates neutrophil homeostasis in pneumonia-derived sepsis caused by Streptococcus pneumoniae serotype 3.

Neutrophil migration to the site of bacterial infection is a critical step in host defense. Exclusively produced in the bone marrow, neutrophil release into the blood is tightly controlled. Although the chemokine CXCL1 induces neutrophil influx during bacterial infections, its role in regulating neutrophil recruitment, granulopoiesis, and neutrophil mobilization in response to lung infection-induced sepsis is unclear. Here, we used a murine model of intrapulmonary Streptococcus pneumoniae infection to investigate the role of CXCL1 in host defense, granulopoiesis, and neutrophil mobilization. Our results demonstrate that CXCL1 augments neutrophil influx to control bacterial growth in the lungs, as well as bacterial dissemination, resulting in improved host survival. This was shown in Cxcl1 -/- mice, which exhibited defective amplification of early neutrophil precursors in granulocytic compartments, and CD62L- and CD49d-dependent neutrophil release from the marrow. Administration of recombinant CXCL2 and CXCL5 after infection rescues the impairments in neutrophil-dependent host defense in Cxcl1 -/- mice. Taken together, these findings identify CXCL1 as a central player in host defense, granulopoiesis, and mobilization of neutrophils during Gram-positive bacterial pneumonia-induced sepsis.

NLRC4 suppresses IL-17A-mediated neutrophil-dependent host defense through upregulation of IL-18 and induction of necroptosis during Gram-positive pneumonia.

Gram-positive pathogens, including Staphylococcus aureus, cause necrotizing pneumonia. The central feature of S. aureus pneumonia is toxin-induced necroptosis of immune and resident cells, which impedes host defense. However, the role of the NLRC4 in the lung following S. aureus infection remains elusive. Here, we demonstrate that S. aureus activates the NLRC4 to drive necroptosis and IL-18 production, which impaired IL-17A-dependent neutrophil-mediated host susceptibility. In particular, Nlrc4-/- mice exhibit reduced necroptosis, enhanced neutrophil influx into the lungs, decreased bacterial burden, and improved host survival. Loss of NLRC4 signaling in both hematopoietic and non-hematopoietic cells contributes to the host protection against S. aureus pneumonia. Secretion of IL-17A by γδ T cells is essential for neutrophil recruitment into the lungs of Nlrc4-/- mice following infection. Moreover, treatment of wild-type mice with necroptosis inhibitors or genetic ablation of MLKL and IL-18 improves host defense against S. aureus infection, which is associated with increased IL-17A+γδ T cells and neutrophils. Taken together, these novel findings reveal that S. aureus activates the NLRC4 to dampen IL-17A-dependent neutrophil accumulation through induction of necroptosis and IL-18. Thus, modulating the function of the NLRC4 may be an attractive therapeutic approach for treating S. aureus infections.