In response to infection, polymorphonuclear neutrophils (PMN) are recruited in the infectious sites, and employ three major strategies to fight against the microbes including phagocytosis, degranulation, and neutrophil extracellular traps (NETs). NETs are a meshwork of chromatin fibers mixed with granule-derived antimicrobial peptides and enzymes, which trap and kill the bacteria extracellularly. In this study, by using a mouse sepsis model, we identified a novel mechanism by which NETs induce macrophage (Mϕ) pyroptosis, a caspase-1-dependent regulated cell death. We show that NET-derived HMGB1, acting through RAGE and dynamin-dependent signaling, triggers an intra-Mϕ cascade of molecular events including cathepsin B (CatB) release from the ruptured lysosomes, followed by pyroptosome formation and caspase-1 activation, and subsequent Mϕ pyroptosis. The study further demonstrates that Mϕ pyroptosis augments inflammatory responses following sepsis. These findings shed light on the proinflammatory role of NETs in mediating PMN–Mϕ interaction, which therefore influences the progress of inflammation following infection.

Group 2 innate lymphoid cells (ILC2) are one of three subgroups of innate lymphoid cells (ILC1, ILC2, and ILC3), and the major ILC population detected in the lungs. The function of ILC2 in the regulation of lung inflammation remains unclear. In the current study, we explored an important role of ILC2 in protecting lung endothelial cell (EC) from pyroptosis in sepsis-induced acute lung inflammation and the underlying mechanism. Using a cecal ligation and puncture (CLP) mouse sepsis model, we demonstrated that IL-33, which is released in response to sepsis, acting through its receptor ST2 mediates ILC2 expansion in the lungs. We further showed that the increased ILC2 in the lungs secrete IL-9, which in turn prevents lung EC from undergoing pyroptosis, a pro-inflammatory cell death form, by attenuating caspase-1 activation. These findings suggest a previously unidentified innate pathway that negatively regulates lung inflammation following sepsis.

Sepsis is a systemic, deleterious host response to widespread infection. Patients with sepsis will have documented or suspected infection which can progress to a state of septic shock or acute organ dysfunction. Since sepsis is responsible for nearly 3 million cases per year in China and severe sepsis is a common, expensive fatal condition in America, developing new therapies becomes a significant and worthwhile challenge. Clinical research has shown that sepsis-associated immunosuppression plays a central role in patient mortality, and targeted immune-enhancing therapy may be an effective treatment approach in these patients. As part of the inflammatory response during sepsis, there are elevations in the number of myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous population of immature myeloid cells that possess immunosuppressive activities via suppressing T-cell proliferation and activation. The role of MDSCs in sepsis remains uncertain. Some believe activated MDSCs are beneficial to the sepsis host by increasing innate immune responses and antimicrobial activities, while others think expansion of MDSCs leads to adaptive immune suppression and secondary infection. Herein, we discuss the complex role of MDSCs in immune regulation during sepsis, as well as the potential to target these cells for therapeutic benefit.

Both bone marrow and adipose-derived mesenchymal stem cells (ASCs) have immunomodulatory effects. The goal of this study was to determine whether ASCs-educated macrophages could directly ameliorate LPS-induced systemic response in a mouse model. Mouse peritoneal macrophages were cocultured with ASCs in a Transwell system for 2 days to educate macrophages. Mice were divided into 5 groups: control, LPS, LPS + ASCs, LPS + untreated macrophages, and LPS + educated macrophages. Educated macrophages decreased lung inflammation, weight loss, pulmonary edema, and inflammatory cytokine response. In vitro, ASCs increased expression of M2 macrophages independent of direct cell-to-cell contact when macrophages were treated with LPS or serum from patients with acute respiratory distress syndrome (ARDS). When macrophages were cultured with serum from ARDS patients who were treated with ASCs or placebo in our previous clinical trial, there was no difference in M2 macrophage levels before and after ASCs treatment indicating a suboptimal response to the treatment protocol. ASCs also reduced the levels of LPS-induced proinflammatory cytokines in vitro which were mimicked by IL-10 and blocked by antibodies for IL-10 and IL-10 receptor supporting the notion that educated macrophages exert their anti-inflammatory effects via IL-10-dependent mechanisms.

Innate lymphoid cells (ILCs), a newly identified member of the lymphoid population, play a critical role in the transition from innate to adaptive immunity in host defense. ILCs are important in mucosal barrier immunity, tissue homeostasis, and immune regulation throughout the body. Significant alterations in ILC responses in lung diseases have been observed and reported. Emerging evidence has shown that ILCs are importantly involved in the pathogenesis and development of a variety of lung diseases, i.e., helminth infections, allergic airway inflammation, and airway hyper-responsiveness. However, as a tissue-resident cell population, the role of ILCs in the lung remains poorly characterized. In this review, we discuss the role of ILCs in lung diseases, the mechanisms underlying the ILC-mediated regulation of immunity, and the therapeutic potential of modulating ILC responses.

BackgroundType 2 immune dysfunction contributes to acute lung injury and lethality following haemorrhagic shock (HS) and trauma. Group 2 innate lymphoid cells (ILC2s) play a significant role in the regulation of type 2 immune responses. However, the role of ILC2 in post-HS acute lung injury and the underlying mechanism has not yet been elucidated.ObjectiveTo investigate the regulatory role of ILC2s in HS-induced acute lung injury and the underlying mechanism in patients and animal model.MethodsCirculating markers of type 2 immune responses in patients with HS and healthy controls were characterised. Using a murine model of HS, the role of high-mobility group box 1 (HMGB1)-receptor for advanced glycation end products (RAGE) signalling in regulation of ILC2 proliferation, survival and function was determined. And the role of ILC2 in inducing type 2 immune dysfunction was assessed as well.ResultsThe number of ILC2s was significantly increased in the circulation of patients with HS that was correlated with the increase in the markers of type 2 immune responses in the patients. Animal studies showed that HMGB1 acted via RAGE to induce ILC2 accumulation in the lungs by promoting ILC2 proliferation and decreasing ILC2 death. The expansion of ILC2s resulted in type 2 cytokines secretion and eosinophil infiltration in the lungs, both of which contributed to lung injury after HS.ConclusionsThese results indicate that HMGB1-RAGE signalling plays a critical role in regulating ILC2 biological function that aggravates type 2 lung inflammation following HS.

BackgroundMesenchymal stem cells (MSCs) have been shown to reduce sepsis-induced inflammation and improve survival in mouse models of sepsis. CD16+ monocytes are proinflammatory and abundant in inflammatory conditions such as sepsis. The primary objective in this exploratory study was to determine the effects of adipose-derived MSCs (ASCs) on three subsets of monocytes from sepsis patients in vitro and to delineate the underlying mechanism.MethodsThis is a prospective cohort study of patients admitted to the medical intensive care unit (ICU) at an academic medical center. The levels of CD14++CD16+, CD14+CD16++, and CD14++CD16– monocytes from 23 patients in the early phase of severe sepsis or septic shock as well as 25 healthy volunteers were determined via flow cytometry after coculture with or without ASCs. To determine the molecular mechanisms, the effects of exogenous prostaglandin E2 (PGE2) and the cyclooxygenase-2 (COX-2) inhibitor NS-398 on monocyte phenotypes and cytokine expression were also examined.ResultsBasal levels of CD14++CD16+ but not CD14+CD16++ monocytes were significantly elevated in severe sepsis and septic shock. A positive linear relationship existed between the levels of CD14++CD16+ monocytes and the Acute Physiology and Chronic Health Evaluation (APACHE) II score as well as Sequential Organ Failure Assessment (SOFA) score. Coculture of ASCs with monocytes from sepsis patients for 24 h significantly reduced CD14++CD16+ expression while increasing the CD14++CD16– phenotype. The coculture also significantly elevated PGE2, COX-2, and prostaglandin E2 receptor (EP)4 levels generated from monocytes. Functionally, ASCs reduced the tumor necrosis factor (TNF)-α and increased the interleukin (IL)-10 secretion in monocytes of septic patients. Furthermore, the effects of ASCs on the CD14++CD16+ phenotype and cytokine expression were mimicked by exogenous PGE2 and abolished by the COX-2 inhibitor NS-398. Additionally, ASCs also modified levels of monocyte phenotypes in a mouse model of sepsis.ConclusionsLevels of CD14++CD16+ monocytes positively correlate with disease severity scores in the early phase of severe sepsis and septic shock. ASCs switch monocytes of sepsis patients from CD14++CD16+ to CD14++CD16– in vitro and modulate the production of inflammatory cytokines. The immunomodulatory effect of ASCs on monocytes is PGE2-dependent. ASCs may exert their therapeutic effect on sepsis via altering monocyte phenotypes and functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0546-x) contains supplementary material, which is available to authorized users.

Intrauterine life represents a window of phenotypic plasticity which carries consequences for later health in adulthood as well as health of subsequent generations. Intrauterine growth-restricted fetuses (intrauterine growth restriction [IUGR]) have a higher risk of pulmonary arterial hypertension in adulthood. Endothelial dysfunction, characterized by hyperproliferation, invasive migration, and disordered angiogenesis, is a hallmark of pulmonary arterial hypertension pathogenesis. Growing evidence suggests that intergenerational transmission of disease, including metabolic syndrome, can be induced by IUGR. Epigenetic modification of the paternal germline is implicated in this transmission. However, it is unclear whether offspring of individuals born with IUGR are also at risk of developing pulmonary arterial hypertension and endothelial dysfunction. Using a model of maternal caloric restriction to induce IUGR, we found that first and second generations of IUGR exhibited elevated pulmonary arterial pressure, myocardial, and vascular remodeling after prolonged exposure to hypoxia. Primary pulmonary vascular endothelial cells (PVECs) from both first and second generations of IUGR exhibited greater proliferation, migration, and angiogenesis. Moreover, in 2 generations, PVECs-derived ET-1 (endothelin-1) was activated by IUGR and hypoxia, and its knockdown mitigated PVECs dysregulation. Most interestingly, within ET-1 first intron, reduced DNA methylation and enhanced tri-methylation of lysine 4 on histone H3 were observed in PVECs and sperm of first generation of IUGR, with DNA demethylation in PVECs of second generation of IUGR. These results suggest that IUGR permanently altered epigenetic signatures of ET-1 from the sperm and PVECs in the first generation, which was subsequently transferred to PVECs of offspring. This mechanism would yield 2 generations with endothelial dysfunction and pulmonary arterial hypertension–like pathophysiological features in adulthood.