|Year : 2019 | Volume
| Issue : 3 | Page : 89-95
Gut Immunity – Homeostasis and Dysregulation in Sepsis
Yini Sun1, Mandy L Ford2, Craig M Coopersmith3
1 Department of Surgery, Emory Critical Care Center, Atlanta, GA, USA; Department of Critical Care Medicine, The First Affiliated Hospital of China Medical University, Shenyang, China
2 Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, GA, USA
3 Department of Surgery, Emory Critical Care Center, Atlanta, GA, USA
|Date of Submission||28-Jun-2019|
|Date of Acceptance||28-Aug-2019|
|Date of Web Publication||28-Oct-2020|
Dr. Craig M Coopersmith
Department of Surgery, Emory Critical Care Center, 101 Woodruff Circle, Suite WMB 5105, Atlanta, GA 30322
The mucosal immune system plays a central role in the pathophysiology of health and disease. As the home to the largest population of lymphocytes in the body, the mucosal immune system closely communicates within other elements of the intestine, with constant cross talk with the gut microbiome and epithelial layer. Further, the gut's immune system plays a central role in communicating with remote organs. The mucosal immune system is critical in preventing autoimmunity, while simultaneously retaining the capacity to respond vigorously to mucosal invaders. This results in a state where the mucosal immune system not only can help restore homeostasis in critical illness but can also worsen inflammation and organ injury in sepsis. The purpose of this minireview is to provide an overview of mucosal immunity in health and in sepsis, with a focus on intraepithelial lymphocytes. Understanding the role of the mucosal immune system in both controlling and propagating sepsis is vital for future efforts designed to target it for therapeutic gain in the intensive care unit.
Keywords: Gut, immune, intestine, mucosa, sepsis
|How to cite this article:|
Sun Y, Ford ML, Coopersmith CM. Gut Immunity – Homeostasis and Dysregulation in Sepsis. J Transl Crit Care Med 2019;1:89-95
| Introduction|| |
The single cell layer intestinal epithelium serves as a barrier between 40 trillion microbes that make up the microbiome and the human host. While the microbiome plays a beneficial role in development and homeostasis, microbes and their products can be deadly if not appropriately compartmentalized. As such, the gut mucosal immune system plays a crucial role in the surveillance of foreign antigens and orchestrating a response when appropriate., This is crucial considering that the mucosal immune system is continuously bombarded with foreign microbial antigens, and the host must perpetually be on watch against invasive pathogens while also allowing the microbiome to not only coexist with the host but also to have bilateral communication with host cells.
To play this crucial role, the mucosal immune system is made up of a number of different cell types that each plays a role in orchestrating the overall host response to acute and chronic antigen stimulation in the gut. The intestine is the largest lymphoid organ of the body, and a variety of immune cells reside between or underneath the epithelial layer. Together, the innate and adoptive immune system communicate and synergize with each other to maintain gut microenvironment homeostasis.
| Gut Immune Cells in Health and Chronic Disease|| |
Intraepithelial lymphocytes (IELs) reside within the gut epithelium where they have immediate access to antigen in the gut lumen and thus function as a specialized antigen-experienced T-cell. There are two types of IELs, with the distinction based on the mechanisms by which they become activated and on the cognate antigens they recognize. Type a IELs (also called induced IELs) are either CD8αβ+ or CD4+ T-cells that express T-cell receptor (TCR)αβ. They arise from conventional T-cells that are activated postthymically in response to peripheral antigen. These represent tissue-resident memory T-cells that are recruited to the epithelium after systemic priming., In contrast, Type b IELs (also called natural IELs), are either CD8αα+ or CD8αα− T-cells that express either TCRαβ or TCRγδ. They acquire their activated phenotype during development in the thymus in the presence of self-antigens and enter the small intestinal epithelium directly upon maturation.
Induced IELs are rare in early life but gradually increase in number with age in response to exogenous antigen.,,,, The development of IELs not only provides protective immunity at the gut mucosa surface but also reduces autoimmune responses directly against innocuous antigens. Natural IELs do not need exogenous antigen so are formed very early in development and thus can be detected in a fetus before birth (before a host is exposed to outside antigen). Over time, a host is exposed to more antigens. As this happens, the population of IELs changes and the host gradually has more Type a IELs than Type b IELs.
A total of 60% of IELs in the small intestine are TCR γδ+. In addition, IELs express the activation markers CD44 and CD69. A hallmark of small intestinal IELs is the expression of CD103 (also known as αE integrin) which interacts with E-cadherin and allows them to home to the small intestine., As might be expected by their location at gut mucosal interface, the presence of microbes in the gut lumen impacts IEL activation and proliferation. Microbial sensing through NOD2 and MyD88 can lead to epithelial production of interleukin (IL)-15, which, in turn, stimulates IEL proliferation and effector function., When IELs are activated, they can express large amounts of biologically active soluble cytokines, such as interferon (IFN)γ, IL-2, IL-4, and IL-17 within hours of activation.,,,,,,,
TCRγδ+ IELs have two (at least) distinct roles in protecting the host. First, these cells control intestinal epithelial cell growth and repair the epithelial barrier.,, As an example, murine colonic IELs promote epithelium barrier function through producing IL-6 in MyD88-dependent manner in response to Citrobacterrodentium infection. In addition, mice lacking TCRγδ+ T-cells have reduced tight junction protein, loss of normal intestinal epithelial cell morphology, reduction of major histocompatibility complex Class II expression by enterocytes, and impairment of mucosal IgA production., TCR γδ+ T-cells also produce keratinocyte growth factor, transforming growth factor-β, and IFNγ, which promotes intestinal epithelial cell proliferation and repair after injury. A complementary role of IELs is immune surveillance in order to avoid mucosal entry of intraluminal microbes and microbial contents. For example, small intestinal γδ+ IELs secrete innate antimicrobial factors in response to resident bacterial pathobionts that penetrate the intestinal epithelium.
Although IELs play important protective and regulatory roles, they also have the potential to cause and/or propagate disease. For instance, Type b γδ+ IELs have been shown to promote immunopathology and inflammation in mice with inflammatory bowel disease.,, In addition, mucosal CD4+-induced IELs can communicate with CD4+ T-cells in the lamina propria to promote the development of small intestine inflammation in patients with celiac diseases.
M cells are located in Peyer's patches, where they comprise 5%–10% of the follicle-associated epithelium. There are short, irregular microvilli on the apical surface of M-cells, which enables them to contact luminal antigen. The intraepithelial pocket beneath the basolateral side of M-cells facilitates pathogen translocation to lymphocytes or antigen-presenting cells, leading to presentation of peptide epitopes to CD4+ T-cells to establish acquired immunity in the gut such that M-cells are “the first entrance” of luminal antigen. M-cells not only play a major role in cross talk with other immune cell population of gut but also provide a platform for developing mucosal vaccines.
Innate lymphoid cells
Innate lymphoid cells (ILCs) are a diverse class of immune cells defined by (a) lymphoid morphology, (b) absence of recombination-associated, gene-mediated antigen receptors, and (c) absence of myeloid and dendritic cell markers. ILCs play a central role in innate immune response to infection, inflammation, and tissue damage, especially in regulating epithelial responses and maintaining intestinal homeostasis. ILCs are divided into three groups based on the cytokine production profile. Group 1 ILCs include natural killer (NK) cells and ILC1 cells and produce IFNγ but no other cytokines associated with Th17 cells. Group 2 ILCs cells are located in the lungs and airways as well as the intestine and mesentery of both humans and mouse and produce TH2- associated cytokines. Group 3 ILCs include all subtypes that produce Th17 cytokines IL-17 and IL-22, which have been implicated in immunity to extracellular bacteria and intestinal inflammation., Signals derived from gut commensal bacteria are recognized by ILC receptors, which can directly regulate ILCs. In addition, selected commensal bacteria reside in dendritic cells and modulate the function of dendritic cells to activate ILC3 cells which subsequently induce the intestinal epithelium to secrete antimicrobial peptides to maintain the balance of intestinal immunity.
The gut is home to the largest population of mast cells in the body. Mast cells regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuroimmune interactions. Microbial translocation leads to mucosal mast cell activation, inflammatory responses, and altered mast cell–enteric nerve interaction. Although an association has been demonstrated between intestinal hyperpermeability and mucosal mast cell activation, the mechanisms linking mast cell activity with altered intestinal barrier in human disease have yet to be elucidated.
Natural killer cells
Intestinal NK cells are scattered in the epithelium and stroma where they contact either microbes or microbial components. In this setting, NK cells interact with epithelial cells, fibroblasts, and multiple different immune cells (macrophages, dendritic cells, and T-lymphocytes). NK cells produce IFNγ, which can lead to recruitment of peripheral NK cells and amplify the host response. While gut NK cells play a role in mucosal immunity, they have also been linked to the pathogenesis of Crohn's disease and ulcerative colitis.
| Gut Immune Dysfunction in Sepsis|| |
Intraepithelial lymphocytes in sepsis
The commonly used intraabdominal sepsis model cecal ligation and puncture (CLP) induces a significant increase of the percentage of CD8+ TCRγδ+ cells with a simultaneous decrease in CD8+ TCRαβ+ percentage. In addition, CLP induces a decline in the ability of IELs to release IL-2 and IFNγ at 24h. This is associated with increased secretion of IL-10 and NO. While no difference was seen in cytokine release in IL-10 knockout mice, this cytokine decline was not seen in iNOS knockout mice, suggesting it is mediated by the NO induction. Early mortality is increased in mice in lacking γδ T-cells following CLP, accompanied by a decrease in plasma IL-6, IL-12, and TNF through suppressing Th1 cytokine release. In addition, CLP induces a lower percentage of CD8αα+ TCRαβ+ IELs and higher messenger RNA expression of complement 5a receptor, IL-2 receptor β, IL-15 receptor α, and IFN-γ by CD8αα+ TCRαβ+ IELs. When septic mice were treated with glutamine, these immunomodulatory-mediator genes decreased and IL-7 receptor and TGB-β expressions increased in CD8αα+ TCRαβ+ IELs associated with decreased apoptosis in CD8αα+ TCRαβ+ IELs. CD8αα+ TCRαβ+ natural IELs express self-reactive TCRs, and under physiological conditions, self-specific CD8αα+ TCRαβ+ IELs protect the intestinal mucosa against chronic inflammation. However, autoreactive IELs might be overactivated in sepsis leading to a higher threshold for TCR activation. Consistent with the contribution of TCRγδ+ IELs in the early host response to infection, these cells limit early bacterial dissemination following infection with Salmonella More Detailsenterica Serovar Typhimurium, as there is a 100-fold increase in bacteria in TCRδ−/− mice compared with wild-type mice 3 h following oral inoculation (although there was no difference at 24–48 h). Similarly, γδ IELs play an essential role in limiting mucosal penetration by intestinal bacteria, associated with production of the antibacterial defensing, RegIIIγ. IELs also have two distinct roles in the response to the murine protozoan pathogen Eimeriavermiformis by production of cytokines to induce protective immunity and expression of junctional molecules to preserve the epithelial barrier. Of note, IELs are kept in a heightened state of activation correlating with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition, and upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. However, when C57Bl/6 mice receive a sublethal dose of LPS, there are no phenotypic changes of IELs. However, IELs display increased cytolytic activity, proliferation, and IFNγ production following LPS administration. Of note, this increased IFNγ production may induce increased NOS-2mRNA seen after endotoxemia.
Innate lymphoid cell 2s in sepsis
Mouse subjected to CLP demonstrated an increase in number and percentage of ILC2s in the small intestine (as well as an increase in the peritoneal cells and a decrease in the liver) 24 h after sepsis. Sepsis also resulted in changes in ILC2 effector cytokine (IL-13) and activating cytokine (IL-33) in the blood of both septic mice and patients in septic shock. These murine changes are abrogated in mice deficient in functionally invariant NKT cells. Further, mice deficient in IL-13-producing cells (including ILC2) have improved survival following sepsis, associated with decreased morphologic evidence of tissue injury and reduced peritoneal IL-10 levels.
Gut immune cross talk
The gut is often referred to as the “motor” of multiple organ dysfunction syndrome. Both the microbiome and the epithelium are extensively injured in sepsis. The microbiome is converted into a pathobiome with a significant loss of diversity and development of numerous virulence factors. The gut epithelium becomes leaky via alterations in tight junctions, leading to hyperpermeability. This is exacerbated by a marked increase in gut epithelial apoptosis, couple with diminished proliferation and slowed migration., None of these processes occurs in isolation, however. A complex “conversation” constantly occurs within the gut as the epithelium, immune system, and microbiome have extensive cross talk, wherein each element profoundly impacts the others, and in turn, is reciprocally impacted.,,,, Of note, IELs have an important role as a first line of defense via cytolysis of dysregulated intestinal epithelial cells and cytokine-mediated regrowth of healthy epithelial cells. In addition, activated IELs provoke Type I/III IFN receptor-dependent upregulation of IFN-responsive genes in the villus epithelium to protect cells against viral infection, such that IEL activation offers a direct means to promote the innate antiviral potential of the intestinal epithelium. In addition, the “gut–lymph hypothesis” postulates that toxic mediators produced in the gut exit via the mesenteric lymph duct, where they cause distant injury in the lung. Ligation of mesenteric lymph duct abrogates lung injury and neutrophil activation, which improves survival in a lethal shock model. In addition, injecting toxic lymph into a healthy animal induces acute lung injury via a TLR4-dependent pathway. Interestingly, gut lymph does not contain intact bacteria or endotoxin, but rather contains protein or lipid factors that stimulate toll-like receptor-4 leading to lung injury.
| Treatments That May Impact Gut Mucosal Immunity in Sepsis|| |
Nutrition support in sepsis
Nutrition support is crucial in sepsis (and critical illnesses in general) in the intensive care unit (ICU). Patients who are not fed have profound immunologic changes, above and beyond the nutritional deficits seen with the obligate catabolic state induced by sepsis. Enteral nutrition augments the host immune response, in addition to its role in providing calories. In addition, route of nutritional administration also significantly impacts the mucosal immune system. Total parenteral nutrition (TPN) in unmanipulated animals induces significant alterations in the phenotypic subpopulations of IELs as well as alterations in IEL gene expression compared to mice that receive enteral nutrition, leading to the potential for significant immunomodulation during the use of TPN. Specifically, 88 IEL genes were upregulated and 114 genes were downregulated in mice receiving TPN. The genes with the highest degree of upregulation were FK506-binding protein 5, mannose-binding lectin, and metallothionein 1, while the genes that had the highest degree of downregulation were microsomal epoxide hydrolase 1 and cytochrome P450 1a1. Nutrition also directly impacts the microbiome, which, in turn, can secondarily alter the immune system. While the majority supporting this link occurs in health, emerging data suggest that nutritional support impacts the microbiome in critical illness as well.
Immunotherapy for sepsis
The success of coinhibition blockade in cancer has led to significant interest in checkpoint inhibitor therapy in sepsis. Robust preclinical data demonstrate that coinhibition blockade – aimed at programmed cell death 1 (PD-1) and its ligand PDL1, cytotoxic T-lymphocyte antigen-4, 2B4, or B- and T-lymphocyte attenuator – improves survival in a wide variety of septic insults.,,,, This has led to the Phase I trials of checkpoint inhibitors in septic patients. The complex and disparate mechanisms through which checkpoint inhibitor blockade improves survival in sepsis is outside the scope of this review. However, it is worth noting that programmed death-ligand 1 (PD-L1) deficiency in mice alters both gut morphology and intestinal permeability following sepsis. Further, PD-L1 knockout mice have reduced tissue levels of IL-6, TNF and MCP-1, as well as prevention of loss of sepsis-induced tight junction protein loss compared to WT mice after sepsis. Further,in vitro evidence demonstrates that PD-L1 expression increases in Caco2 cell monolayers in response to inflammatory cytokine stimulation associated with increased monolayer permeability, while these changes are reversed by blocking PD-L1.
As an immune-boosting agent, IL-7 can lead to the production of naïve T-cells, memory T-cells, central memory T-cells, and CD4+ CD8+ T-cells. Preclinical data demonstrate that IL-7 improves T-cell viability, trafficking, and IFNγ production and leads to a two-fold improvement in survival in mice with polymicrobial sepsis. IL-7 also improves host immunity and survival in a two-hit model of Pseudomonasaeruginosa pneumonia. In addition, a Phase I clinical trial of IL-7 in septic patients demonstrated encouraging results, with a reversal of loss of CD4+ and CD8+ cells. Although the mechanism of IL-7 is complex, IL-7 has been demonstrated to modulate the composition of gut ILCs, suggesting that altering mucosal immunity might play a role in the efficacy of IL-7.
The amino acid glutamine modulates the mucosal immune system in sepsis. A single intravenous dose of glutamine following CLP increases the percentage of CD8αα+ TCRαβ+ IELs, prevents CD8αα+ TCRαβ+ IELs apoptosis, and downregulates CD8αα+ TCRαβ+ IEL-expressed inflammatory mediators, including C5aR, IL-2Rβ, IL-15Rα, and IFNγ. In addition, glutamine prevents TPN-associated IEL-derived cytokine changes, upregulates tight junction protein expression, and preserves the epithelial barrier function. Unfortunately, despite significant preclinical trials supporting its use as well as smaller clinical trials, the largest clinical trial of glutamine in critical illness demonstrated increased mortality in patients randomized to receive glutamine, while supplementing parenteral nutrition with glutamine did not change outcomes in surgical ICU patients. As such, despite its beneficial effects on gut mucosal immunity (and overall gut homeostasis) in murine studies, additional studies are needed to determine if there is a role for glutamine in septic patients.
| Conclusion|| |
The mucosal immune system has a unique role in maintaining health and mediating disease due to its close connections with the gut epithelium, the gut microbiome, as well as the systemic immune system. In its location at the interface of multiple critical biological processes, the mucosal immune system can either help restore homeostasis or propagate disease via alterations in inflammation. Further studies are needed to better understand the role of the mucosal immune system in the pathophysiology and sepsis and whether it can be targeted for therapeutic gain.
Financial support and sponsorship
This work was supported by funding from the National Institutes of Health (GM072808, GM104323, AA027396, GM113228).
Conflicts of interest
There are no conflicts of interest.
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