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Abstract The regeneration of epithelia is crucial for maintaining intestinal homeostasis. Irisin is an exercise-induced hormone originally found to be secreted by skeletal muscles, thereby regulating energy metabolism. Recent studies have revealed that irisin protected against gut inflammation. However, the direct effects of irisin on the intestinal epithelial cells remain to be elucidated. In this study, mouse intestinal organoids were used to assess the effects of irisin on the proliferation of the intestinal epithelial cells. At a concentration of 100 ng/mL irisin significantly increased the growth of the intestinal organoids and upregulated the Wnt/β-catenin and focal adhesion kinase (FAK) signaling pathway genes. Notably, a FAK inhibitor 14 blocked the effects of irisin on the proliferation of the intestinal epithelial cells by inhibiting FAK phosphorylation, as well as the expressions of Wnt target genes. Furthermore, irisin (100 ng/mL) improved the recovery of the intestinal organoids from cellular damages caused by TNF-α, and markedly increased the expression of Wnt target genes in the intestinal epithelial cells. Taken together, irisin activates Wnt/β-catenin and FAK signaling pathways in the intestinal epithelial cells, thereby promoting intestinal epithelial self-renewal under normal homeostatic conditions and intestinal epithelial regeneration upon damages.

Abstract Background Intensive care unit‐acquired weakness (ICU‐AW) is a syndrome characterized by a long‐term muscle weakness often observed in sepsis‐surviving patients during the chronic phase. Although ICU‐AW is independently associated with increased mortality, effective therapies have yet to be established. Programmed death‐1 (PD‐1) inhibitors have attracted attention as potential treatments for reversing immune exhaustion in sepsis; however, its impact on ICU‐AW remains to be elucidated. Here, we study how PD‐1 deficiency affects sepsis‐induced skeletal muscle dysfunction in a preclinical sepsis model. Methods Chronic sepsis model was developed by treating wild‐type (WT) and PD‐1 knockout (KO) mice with caecal slurry, followed by resuscitation with antibiotics and saline. Mice were euthanized on days 15–17. Body weights, muscle weights, and limb muscle strengths were measured. Interleukin 13 (IL‐13) and PD‐1 expressions were examined by flow cytometry. Messenger RNA (mRNA) expressions of slow‐twitch muscles were measured by reverse transcription and quantitative polymerase chain reaction (RT‐qPCR). In an in vitro study, C2C12 myotubes were treated with lipopolysaccharide (LPS) and recombinant IL‐13 followed by gene expression measurements. Results WT septic mice exhibited decreased muscle weight (quadriceps, P

With the increasing demand for highly efficient lighting in the automotive industry, flip-chip light-emitting diodes (LEDs) have become widely used for both interior and exterior lighting. Solder, serving as a crucial interconnecting material, often develops voids during the reflow process, compromising the integrity and reliability of the connections. Thus, understanding the impact of these voids on the mechanical and thermal properties of the product is vital for improving reliability accuracy. This work employs computational methods alongside experimental approaches to address the challenges of replicating solder voids and controlling the solder void fraction. A comprehensive study investigates the effects of solder voids on shearing properties and thermal conductance. Random voids were introduced into the solder pads of an LED assembly within a finite element model (FEM), leading to predictions of maximum shear stress and LED junction temperature. The findings correlate well with the experimental data, validating the FEM's applicability. Furthermore, a statistical analysis was conducted to explore the relationship between solder void fraction, position, and size, aiming to provide objective guidelines for analyzing soldered assembly tomography in reliability assessments.

BackgroundEffective communication strategies are becoming increasingly important in intensive care units (ICUs) where patients at high risk are treated. Distributed leadership promotes effective communication among health care professionals (HCPs). Moreover, beyond facilitating patient care, it may improve well-being among HCPs by fostering teamwork. However, the impact of distributed leadership on the communication structure and well-being of HCPs remains unclear. ObjectiveWe performed a social network analysis (SNA) to assess the characteristics of each HCP in the network, identify the number of HCP connections, analyze 4 centralities that can measure an HCP’s importance, and evaluate the impact of distributed leadership structure on the well-being and communication structure of the medical staff. MethodsWearable sensors were used to obtain face-to-face interaction data from the ICU medical staff at Mie University Hospital, Japan. Participants wore a badge on the front of their clothing during working hours to measure the total frequency of face-to-face interactions. We collected data about the well-being of medical staff using the Center for Epidemiological Studies–Depression (CES-D) questionnaire and measured 4 centralities using SNA analysis. A CES-D questionnaire was administered during the study to measure the well-being of the HCPs. ResultsOverall, 247 ICU workers participated in this clinical study for 4 weeks yearly in February 2016, 2017, and 2018. The distributed leadership structure was established within the ICU in 2017 and 2018. We compared these results with those of the traditional leadership structure used in 2016. Most face-to-face interactions in the ICU were among nurses or between nurses and other professionals. In 2016, overall, 10 nurses could perform leadership tasks, which significantly increased to 24 in 2017 (P=.046) and 20 in 2018 (P=.046). Considering the increased number of nurses who could perform leadership duties and the collaboration created within the organization, SNA in 2018 showed that the betweenness (P=.001), degree (P

Abstract The ability of integrins on the cell surface to mediate cell adhesion to the extracellular matrix ligands is regulated by intracellular signaling cascades. During this signaling process, the talin (TLN) recruited to integrin cytoplasmic tails plays the critical role of the major adaptor protein to trigger integrin activation. Thus, intracellular levels of TLN are thought to determine integrin-mediated cellular functions. However, the epigenetic regulation of TLN expression and consequent modulation of integrin activation remain to be elucidated. Bioinformatics analysis led us to consider miR-200c-3p as a TLN1-targeting miRNA. To test this, we have generated miR-200c-3p-overexpressing and miR-200c-3p-underexpressing cell lines, including HEK293T, HCT116, and LNCaP cells. Overexpression of miR-200c-3p resulted in a remarkable decrease in the expression of TLN1, which was associated with the suppression of integrin-mediated cell adhesion to fibronectin. In contrast, the reduction in endogenous miR-200c-3p levels led to increased expression of TLN1 and enhanced cell adhesion to fibronectin and focal adhesion plaques formation. Moreover, miR-200c-3p was found to target TLN1 by binding to its 3′-untranslated region (UTR). Taken together, our data indicate that miR-200c-3p contributes to the regulation of integrin activation and cell adhesion via the targeting of TLN1.

Intestinal epithelial cells (IECs) are a mucosal immune barrier essential to coordinate host–microbe crosstalk. Sepsis is a systemic inflammatory syndrome with dysfunction in multiple organs including the intestine whose epithelial barrier is deregulated. Thus, IECs are a main contributor to intestinal permeability and inflammation in sepsis. Exosomes emerge as a mediator of intercellular and inter-organic communications. Recently, IEC-derived exosomes and their cargoes, such as microRNAs (miRNAs), in sepsis were shown to regulate the expression of proinflammatory mediators in the inflamed gut tissues. It is a compelling hypothesis that these IEC exosomes exhibit their dynamic activity to deliver their functional miRNA cargoes to immune cells in local and distant organs to regulate proinflammatory responses and alleviate tissue injury. Also, epithelial tight junction (TJ) proteins are downregulated on gut inflammation. Some of the IEC miRNAs were reported to deteriorate the epithelial integrity by diminishing TJ expressions in intestines during sepsis and aging. Thus, it is worth revisiting and discussing the diverse functions of IEC exosomes and miRNAs in reshaping inflammations. This review includes both iterative and hypothetical statements based on current knowledge in this field.

Abstract Exosomes represent an important subset of extracellular vesicles involved in inter-cellular communications in health and diseases. Exosomes secreted from cancer and immune cells travel to the specific tissues containing homing niches. The exosomes reaching the niches dynamically modify the gene expression and molecular architectures of the homing niche micro-environments. Cell adhesion molecule integrins regulate the tissue-specific homing patterns of not only cancer and immune cells, but also of the exosomes secreted from those cells. The exosome-mediated remodeling of the homing niches would affect immune lymphocyte migration and host defense, as well as cancer metastasis, thereby representing a potential therapeutic target.

The revolutionary concept of creating a large‐area tactile sensor by training a simple, bulky material through deep learning (DL) is proposed. This enables the replacement of the conventional tactile sensor comprising a patterned array structure with a super‐simple, single‐layer, large‐area tactile sensor pad. A crude carbon nanotube‐dispersed polydimethylsiloxane pad—with a bias applied to the center and the resultant piezoresistive current detected at several electrodes located on the pad edge—plays a smart sensory role without the need for complicated fabrication of microengineered structures. The piezoresistive current while recording the indented location and the pressure thereon is measured, and then various DL models (a multimodel arrangement is necessary due to the viscoelasticity of the pad) using the collected data are trained. The proposed concept is realized using a tandem model comprising a combination of algorithms selected from deep neural networks, convolutional neural networks, long short‐term memory networks, and 16 state‐of‐the‐art machine learning algorithms. The hold‐out dataset test accuracy for the indented location identification reaches 98.89%, and the goodness of fit for pressure prediction is evaluated with mean squared error of 2.5 × 10−3 and coefficient of determination of 98.05%.

Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IECs were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively target LOX, PTCH1, COL22A1, FOXO1, or HMGA2, via in silico analysis, which were associated with Wnt or inflammatory pathways and selected for further study. The expressions of these target genes were downregulated in sepsis IECs, possibly through posttranscriptional modifications of these miRNAs. Taken together, our study suggests that IECs display a distinctive miRNA profile which is capable of comprehensively and functionally reshaping the IEC-specific mRNA landscape in a sepsis model.

Expression of chemokine receptor CX3CR1 is reportedly restricted to several cell types including natural killer cells, cytotoxic T cells, monocytes, and macrophages. However, its expression and function on exosomes, which are nanosized extracellular vesicles known to act as mediators of intercellular communications, remain unclear. Here, we investigated CX3CR1 expression on exosomes isolated from various cell types. Although we found that all the exosomes tested in our study highly expressed CX3CR1, this chemokine receptor was expressed only inside, but barely on, their source cells. Moreover, exosomal CX3CR1 was capable of binding soluble CX3CL1. Therefore, our study suggests that CX3CR1 is a novel and ligand-competent exosome receptor.

Irisin, a myokine released from skeletal muscle, has recently been found to act as a ligand for the integrins αVβ5, αVβ1, and α5β1 expressed on mesenchymal cells, thereby playing an important role in the metabolic remodeling of the bone, skeletal muscle and adipose tissues. Although the immune-modulatory effects of irisin in chronic inflammation have been documented, its interactions with lymphocytic integrins have yet to be elucidated. Here, we show that irisin supports the cell adhesion of human and mouse lymphocytes. Cell adhesion assays using a panel of inhibitory antibodies to integrins have shown that irisin-mediated lymphocyte adhesion involves multiple integrins including not only α4β1 and α5β1, but also leukocyte-specific αLβ2 and α4β7. Importantly, mouse lymphocytic TK-1 cells that lack the expression of β1 integrins have exhibited αLβ2- and α4β7-mediated cell adhesion to irisin. Irisin has also been demonstrated to bind to purified recombinant integrin αLβ2 and α4β7 proteins. Thus, irisin represents a novel ligand for integrin αLβ2 and α4β7, capable of supporting lymphocyte cell adhesion independently of β1 integrins. These results suggest that irisin may play an important role in regulating lymphocyte adhesion and migration in the inflamed vasculature.

Abstract Background Insertion under laryngoscopic guidance has been used to achieve ideal positioning of the laryngeal mask airway (LMA). However, to date, the efficacy of this technique has been evaluated only using fiberoptic evaluation, and the results have been conflicting. Other reliable tests to evaluate the efficacy of this technique have not been established. Recently, it has been suggested that the accuracy of LMA placement can be determined by clinical signs such as oropharyngeal leak pressure (OPLP). The aim of this study was to assess the efficacy of LMA insertion under laryngoscopic guidance using OPLP as an indicator. Methods After approved by the institutional ethics committee, a prospective comparison of 100 patients divided into 2 groups (50 with blind technique and 50 with the laryngoscope technique) were evaluated. An LMA (LarySeal™, Flexicare medical Ltd., UK) was inserted using the blind approach in the blind insertion group and using laryngoscopy in the laryngoscope-guided insertion group. The OPLP, fiberoptic position score, whether the first attempt at LMA insertion was successful, time taken for insertion, ease of LMA insertion, and adverse airway events were recorded. Results Data were presented as mean ± standard deviation. The OPLP was higher in the laryngoscope-guided insertion group than in the blind insertion group (21.4 ± 8.6 cmH2O vs. 18.1 ± 6.1 cmH2O, p = 0.031). The fiberoptic position score, rate of success in the first attempt, ease of insertion, and pharyngolaryngeal adverse events were similar between both groups. The time taken for insertion of the LMA was significantly longer in the laryngoscope-guided insertion group, compared to blind insertion group (35.9 ± 9.5 s vs. 28.7 ± 9.5 s, p

Extracellular vesicles (EVs) have emerged as key players of intercellular communication and mediate crosstalk between tissues. Metastatic tumors release tumorigenic EVs, capable of pre-conditioning distal sites for organotropic metastasis. Growing evidence identifies muscle cell-derived EVs and myokines as potent mediators of cellular differentiation, proliferation, and metabolism. Muscle-derived EVs cargo myokines and other biological modulators like microRNAs, cytokines, chemokines, and prostaglandins hence, are likely to modulate the remodeling of niches in vital sites, such as liver and adipose tissues. Despite the scarcity of evidence to support a direct relationship between muscle-EVs and cancer metastasis, their indirect attribution to the regulation of niche remodeling and the establishment of pre-metastatic homing niches can be put forward. This hypothesis is supported by the role of muscle-derived EVs in findings gathered from other pathologies like inflammation and metabolic disorders. In this review, we present and discuss studies that evidently support the potential roles of muscle-derived EVs in the events of niche pre-conditioning and remodeling of metastatic tumor microenvironment. We highlight the potential contributions of the integrin-mediated interactions with an emerging myokine, irisin, to the regulation of EV-driven microenvironment remodeling in tumor metastasis. Further research into muscle-derived EVs and myokines in cancer progression is imperative and may hold promising contributions to advance our knowledge in the pathophysiology, progression and therapeutic management of metastatic cancers.

Sepsis remains a major problem for human health worldwide, thereby manifesting high rates of morbidity and mortality. Sepsis, once understood as a monophasic sustained hyperinflammation, is currently recognized as a dysregulated host response to infection, with both hyperinflammation and immunoparalysis occurring simultaneously from the earliest stages of sepsis, involving multiple organ dysfunctions. Despite the recent progress in the understanding of the pathophysiology underlying sepsis, no specific treatment to restore immune dysregulation in sepsis has been validated in clinical trials. In recent years, treatment for immune checkpoints such as the programmed cell death protein 1/programmed death ligand (PD-1/PD-L) pathway in tumor-infiltrating T-lymphocytes has been successful in the field of cancer immune therapy. As immune-paralysis in sepsis involves exhausted T-lymphocytes, future clinical applications of checkpoint inhibitors for sepsis are expected. In addition, the functions of PD-1/PD-L on innate lymphoid cells and the role of exosomal forms of PD-L1 warrant further research. Looking back on the history of repeatedly failed clinical trials of immune modulatory therapies for sepsis, sepsis must be recognized as a difficult disease entity for performing clinical trials. A major obstacle that could prevent effective clinical trials of drug candidates is the disease complexity and heterogeneities; clinically diagnosed sepsis could contain multiple sepsis subgroups that suffer different levels of hyper-inflammation and immune-suppression in distinct organs. Thus, the selection of appropriate more homogenous sepsis subgroup is the key for testing the clinical efficacy of experimental therapies targeting specific pathways in either hyperinflammation and/or immunoparalysis. An emerging technology such as artificial intelligence (AI) may help to identify an immune paralysis subgroup who would best be treated by PD-1/PD-L1 pathway inhibitors.

Integrins are transmembrane proteins that mediate cellular adhesion and migration to neighboring cells or the extracellular matrix, which is essential for cells to undertake diverse physiological and pathological pathways. For integrin activation and ligand binding, bidirectional signaling across the cell membrane is needed. Integrins aberrantly activated under pathologic conditions facilitate cellular infiltration into tissues, thereby causing inflammatory or tumorigenic progressions. Thus, integrins have emerged to the forefront as promising targets for developing therapeutics to treat autoimmune and cancer diseases. In contrast, it remains a fact that integrin-ligand interactions are beneficial for improving the health status of different tissues. Among these ligands, irisin, a myokine produced mainly by skeletal muscles in an exercise-dependent manner, has been shown to bind to integrin αVβ5, alleviating symptoms under unfavorable conditions. These findings may provide insights into some of the underlying mechanisms by which exercise improves quality of life. This review will discuss the current understanding of integrin-ligand interactions in both health and disease. Likewise, we not only explain how diverse ligands play different roles in mediating cellular functions under both conditions via their interactions with integrins, but also specifically highlight the potential roles of the emerging ligand irisin in inflammation, cancer, and metabolic disease.

Abstract Endothelial monolayers have shown the ability to signal each other through gap junctions. Gap junction-mediated cell-cell interactions have been implicated in the modulation of endothelial cell functions during vascular inflammation. Inflammatory mediators alter the mechanical properties of endothelial cells, although the exact role of gap junctions in this process remains unclear. Here, we sought to study the role of gap junctions in the regulation of endothelial stiffness, an important physical feature that is associated with many vascular pathologies. The endothelial cellular stiffness of living endothelial cells was determined by using atomic force microscopy. We found that tumor necrosis factor-α transiently increased endothelial cellular stiffness, which is regulated by cytoskeletal rearrangement and cell-cell interactions. We explored the role of gap junctions in endothelial cellular stiffening by utilizing gap junction blockers, carbenoxolone, inhibitory anti-connexin 32 antibody or anti-connexin 43 antibody. Blockade of gap junctions induced the cellular stiffening associated with focal adhesion formation and cytoskeletal rearrangement, and prolonged tumor necrosis factor-α-induced endothelial cellular stiffening. These results suggest that gap junction-mediated cell-cell interactions play an important role in the regulation of endothelial cellular stiffness.

The spike glycoprotein attached to the envelope of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to and exploits angiotensin-converting enzyme 2 (ACE2) as an entry receptor to infect pulmonary epithelial cells. A subset of integrins that recognize the arginyl–glycyl–aspartic acid (RGD) sequence in the cognate ligands has been predicted in silico to bind the spike glycoprotein and, thereby, to be exploited for viral infection. Here, we show experimental evidence that the β1 integrins predominantly expressed on human pulmonary epithelial cell lines and primary mouse alveolar epithelial cells bind to this spike protein. The cellular β1 integrins support adhesive interactions with the spike protein independently of ACE2, suggesting the possibility that the β1 integrins may function as an alternative receptor for SARS-CoV-2, which could be targeted for the prevention of viral infections.

Thrombomodulin is a molecule with anti-coagulant and anti-inflammatory properties. Recently, thrombomodulin was reported to be able to bind extracellular matrix proteins, such as fibronectin and collagen; however, whether thrombomodulin regulates the binding of human breast cancer-derived cell lines to the extracellular matrix remains unknown. To investigate this, we created an extracellular domain of thrombomodulin, TMD123-Fc, or domain deletion TM-Fc proteins (TM domain 12-Fc, TM domain 23-Fc) and examined their bindings to fibronectin in vitro by ELISA. The lectin-like domain of thrombomodulin was found to be essential for the binding of the extracellular domain of thrombomodulin to fibronectin. Using a V-well cell adhesion assay or flow cytometry analysis with fluorescent beads, we found that both TMD123-Fc and TMD12-Fc inhibited the binding between β1 integrin of human breast cancer-derived cell lines and fibronectin. Furthermore, TMD123-Fc and TMD12-Fc inhibited the binding of activated integrins to fibronectin under shear stress in the presence of Ca2+ and Mg2+ but not under strong integrin-activation conditions in the presence of Mg2+ without Ca2+. This suggests that thrombomodulin Fc fusion protein administered exogenously at a relatively early stage of inflammation may be applied to the development of new therapies that inhibit the binding of β1 integrin of breast cancer cell lines to fibronectin.

Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin are tetrahydrofurofuranoid lignans with various pharmacological activities found in Magnoliae Flos. The inhibition potencies of eudesmin, fargesin, epimagnolin A, magnolin, and yangambin on six major human uridine 5′-diphospho-glucuronosyltransferase (UGT) activities in human liver microsomes were evaluated using liquid chromatography–tandem mass spectrometry and cocktail substrates. Eudesmin, fargesin, epimagnolin A, magnolin, and yangambin inhibited UGT1A1 and UGT1A3 activities, but showed negligible inhibition of UGT1A4, UGT16, UGT1A9, and UGT2B7 activities at 200 μM in pooled human liver microsomes. Moreover, eudesmin, fargesin, epimagnolin A, magnolin, and yangambin noncompetitively inhibited UGT1A1-catalyzed SN38 glucuronidation with Ki values of 25.7, 25.3, 3.6, 26.0, and 17.1 μM, respectively, based on kinetic analysis of UGT1A1 inhibition in pooled human liver microsomes. Conversely, the aforementioned tetrahydrofurofuranoid lignans competitively inhibited UGT1A3-catalyzed chenodeoxycholic acid 24-acyl-glucuronidation with 39.8, 24.3, 15.1, 37.6, and 66.8 μM, respectively in pooled human liver microsomes. These in vitro results suggest the necessity of evaluating whether the five tetrahydrofurofuranoid lignans can cause drug–drug interactions with UGT1A1 and UGT1A3 substrates in vivo.

Indazole carboxamide synthetic cannabinoid, AB-PINACA, has been placed into Schedule I of the Controlled Substances Act by the US Drug Enforcement Administration since 2015. Despite the possibility of AB-PINACA exposure in drug abusers, the interactions between AB-PINACA and drug-metabolizing enzymes and transporters that play crucial roles in the pharmacokinetics and efficacy of various substrate drugs have not been investigated. This study was performed to investigate the inhibitory effects of AB-PINACA on eight clinically important human major cytochrome P450s (CYPs) and six uridine 5′-diphospho-glucuronosyltransferases (UGT) in human liver microsomes and the activities of six solute carrier transporters and two efflux transporters in transporter-overexpressing cells. AB-PINACA reversibly inhibited the metabolic activities of CYP2C8 (Ki, 16.9 µM), CYP2C9 (Ki, 6.7 µM), and CYP2C19 (Ki, 16.1 µM) and the transport activity of OAT3 (Ki, 8.3 µM). It exhibited time-dependent inhibition on CYP3A4 (Ki, 17.6 µM; kinact, 0.04047 min−1). Other metabolizing enzymes and transporters such as CYP1A2, CYP2A6, CYP2B6, CYP2D6, UGT1A1, UGT1A3, UGT1A4, UGT1A6, UGT1A9, UGT2B7, OAT1, OATP1B1, OATP1B3, OCT1, OCT2, P-glycoprotein, and BCRP, exhibited only weak interactions with AB-PINACA. These data suggest that AB-PINACA can cause drug-drug interactions with CYP3A4 substrates but that the significance of drug interactions between AB-PINACA and CYP2C8, CYP2C9, CYP2C19, or OAT3 substrates should be interpreted carefully.

Septic shock/severe sepsis is a deregulated host immune system response to infection that leads to life-threatening organ dysfunction. Lung inflammation as a form of acute lung injury (ALI) is often induced in septic shock. Whereas macrophages and neutrophils have been implicated as the principal immune cells regulating lung inflammation, group two innate lymphoid cells (ILC2s) have recently been identified as a new player regulating immune homeostasis. ILC2 is one of the three major ILC subsets (ILC1s, ILC2s, and ILC3s) comprised of newly identified innate immune cells. These cells are characterized by their ability to rapidly produce type 2 cytokines. ILC2s are predominant resident ILCs and, thereby, have the ability to respond to signals from damaged tissues. ILC2s regulate the immune response, and ILC2-derived type 2 cytokines may exert protective roles against sepsis-induced lung injury. This focused review not only provides readers with new insights into the signaling mechanisms by which ILC2s modulate sepsis-induced lung inflammation, but also proposes ILC2 as a novel therapeutic target for sepsis-induced ALI.

Sepsis is a systemically dysregulated inflammatory syndrome, in which dendritic cells (DCs) play a critical role in coordinating aberrant immunity. The aim of this study is to shed light on the differential roles played by systemic versus mucosal DCs in regulating immune responses in sepsis. We identified a differential impact of the systemic and mucosal DCs on proliferating allogenic CD4 T cells in a mouse model of sepsis. Despite the fact that the frequency of CD4 T cells was reduced in septic mice, septic mesenteric lymph node (MLN) DCs proved superior to septic spleen (SP) DCs in expanding allogeneic CD4 T cells. Moreover, septic MLN DCs markedly augmented the surface expression of MHC class II and CD40, as well as the messaging of interleukin-1β (IL-1β). Interestingly, IL-1β-treated CD4 T cells expanded in a dose-dependent manner, suggesting that this cytokine acts as a key mediator of MLN DCs in promoting septic inflammation. Thus, mucosal and systemic DCs were found to be functionally different in the way CD4 T cells respond during sepsis. Our study provides a molecular basis for DC activity, which can be differential in nature depending on location, whereby it induces septic inflammation or immune-paralysis.