Exosomes secreted from T cells have been shown to affect dendritic cells, cancer cells, and other T cells. However, little is known about how T-cell exosomes (T exosomes) modulate endothelial cell functions in the context of tissue-specific homing. Here, we study the roles of T exosomes in the regulation of gut-specific T-cell homing. The gut-tropic T cells induced by retinoic acid secrete the exosomes that upregulate integrin α4β7 binding to the MAdCAM-1 expressed on high endothelial venules in the gut. T exosomes were preferentially distributed to the villi of the small intestine in an α4β7-dependent manner. Exosomes from gut-tropic T cells suppressed the expression of MAdCAM-1 in the small intestine, thereby inhibiting T-cell homing to the gut. Moreover, microRNA (miRNA) profiling analysis has shown that exosomes from gut-tropic T cells were enriched with miRNAs targeting NKX2.3, a transcription factor critical to MAdCAM-1 expression. Taken together, our study proposes that α4β7-expressing T exosomes distribute themselves to the small intestine and modify the expression of microenvironmental tissues such that any subsequent lymphocyte homing is precluded. This may represent a novel mechanism by which excessive lymphocyte homing to the intestinal tissues is downsized.
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.
Extracellular vesicles (EVs) in the plasma mediate important inter-cellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programed cell-1 ligand 1 and 2 (PD-L1 and 2) that suppress lymphocyte activation. However, the roles of these molecules on EVs in systemic inflammatory response syndrome (SIRS) and sepsis remain little understood. This study aimed to investigate how the EV expression of integrins and PD-1 ligands might differ in SIRS and sepsis, compared with healthy controls, and to correlate their expression with the clinical parameters reflecting pathogenesis. Twenty-seven SIRS patients without sepsis, 27 sepsis patients, and 18 healthy volunteers were included. EVs were isolated from plasma samples. The expression of three major integrins (β1, β2, β3 integrins) and PD-L1 and 2 were measured. The EV expression of β2 integrin and PD-L2 was significantly increased in sepsis patients compared with healthy controls. EV expression of PD-L1 was not elevated in sepsis and SIRS; however, circulating soluble PD-L1 levels were significantly higher in sepsis. Furthermore, EV expression of β2 integrin in sepsis patients correlated with hypotension and reduced kidney function. In addition, soluble PD-L1 levels correlated with sepsis severity, impaired kidney function, and impaired central nervous system function. These results suggest the potential involvements of the EV β2 integrin, as well as EV PD-L2 and soluble PD-L1, in the septic pathogenesis that occurs with the systemic immune activation leading to multiple organ dysfunctions.
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.
Sepsis is a systemic inflammatory disorder induced by a dysregulated immune response to infection resulting in dysfunction of multiple critical organs, including the intestines. Previous studies have reported contrasting results regarding the abilities of exosomes circulating in the blood of sepsis mice and patients to either promote or suppress inflammation. Little is known about how the gut epithelial cell-derived exosomes released in the intestinal luminal space during sepsis affect mucosal inflammation. To study this question, we isolated extracellular vesicles (EVs) from intestinal lavage of septic mice. The EVs expressed typical exosomal (CD63 and CD9) and epithelial (EpCAM) markers, which were further increased by sepsis. Moreover, septic-EV injection into inflamed gut induced a significant reduction in the messaging of pro-inflammatory cytokines TNF-α and IL-17A. MicroRNA (miRNA) profiling and reverse transcription and quantitative polymerase chain reaction (RT-qPCR) revealed a sepsis-induced exosomal increase in multiple miRNAs, which putatively target TNF-α and IL-17A. These results imply that intestinal epithelial cell (IEC)-derived luminal EVs carry miRNAs that mitigate pro-inflammatory responses. Taken together, our study proposes a novel mechanism by which IEC EVs released during sepsis transfer regulatory miRNAs to cells, possibly contributing to the amelioration of gut inflammation.
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.
Deregulation of the immune system in sepsis plays the central role in the pathogenesis of multiple organ failure including septic lung injury. Group 2 innate lymphoid cells (ILC2s) have emerged as a new player in regulating immune homeostasis in the lung; however, the role of ILC2s in lung injury in sepsis remains poorly understood. Here, we investigated temporal changes in stimulatory and inhibitory receptor expression and intracellular type 2 cytokine expression of ILC2s in the lung using a cecal ligation and puncture mouse sepsis model. We found that IL-13 production by ILC2s, which were predominately composed of the resident natural ILC2 subset rather than the migratory inflammatory ILC2 subset, was reduced in the lungs of sepsis mice on day 1 and gradually restored through day 7. Although the expression levels of ST2 and inducible T-cell costimulator (stimulatory receptors) were high, IL-13 production by ILC2s was reduced while showing high programmed cell death 1 (PD-1) (inhibitory receptor) expression. Furthermore, using IL-33 knockout mice, we have shown that IL-33 regulates the capacity of ILC2s to produce IL-13, possibly through the modulation of ST2 and PD-1 expression and signaling in the septic lung. To the best of our knowledge, this is the first report showing differential costimulatory/inhibitory receptor expression on ILC2s in a septic lung in the context of an IL-33/IL-13 pathway-mediated type 2 immune response in the progression and resolution of inflammation. Our present findings contribute to a better understanding of the underlying immunological mechanism of ILC2s and may fill the critical knowledge gap regarding immune homeostasis in the lung that hampers the development of new therapeutic strategies for sepsis-induced acute lung injury.
Asymptomatic bacteriuria (ASB) is benign except in certain medical conditions such as pregnancy and immunosuppression. In Ghana, there are hardly any studies on urinary infections among sickle cell disease (SCD) patients, and the few studies carried out in Africa focused on pediatric SCD populations. The current study aimed to investigate the risk of ASB among SCD patients at a tertiary hospital in Ghana. This was a cross-sectional study involving 110 SCD patients and 110 age and sex matched healthy controls. Urine specimens were collected from all the study subjects and analyzed by standard microbiological methods. Demographic information were also collected from the study subjects. The overall ASB prevalence was significantly higher among SCD patients (17.2%) than among the control group (8.2%), and the relative risk was 2.11 (p = 0.0431; CI = 1.00-4.45). Being female was as a predictor of ASB among the SCD patients (OR = 14.76; CI = 11.23-18.29; p = 0.0103). The most common organism isolated from the study participants was coagulase negative Staphylococcus species (4.1%), followed by Escherichia coli (2.7%); etiology of ASB in the SCD patients was more diverse compared to healthy people. All the E. coli isolates were susceptible to amikacin, sparfloxacin and norfloxacin but resistant to ampicillin.
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