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Immunosuppression is Inappropriately Qualifying the Immune Status of Septic and SIRS Patients

Cavaillon, Jean-Marc*; Giamarellos-Bourboulis, Evangelos J.

doi: 10.1097/SHK.0000000000001266
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ABSTRACT Immunosuppression is the most commonly used concept to qualify the immune status of patients with either sterile systemic inflammatory response syndrome (SIRS) or sepsis. In this review we attempt to demonstrate that the concept of immunosuppression is an oversimplification of the complex anti-inflammatory response that occurs in patients dealing with a severe sterile or infectious insult. Particularly, the immune status of leukocytes varies greatly depending on the compartment from where they are derived from. Furthermore, although certain functions of immune cells present in the blood stream or in the hematopoietic organs can be significantly diminished, other functions are either unchanged or even enhanced. This juxtaposition illustrates that there is no global defect. The mechanisms called reprogramming or trained innate immunity are probably aimed at preventing a generalized deleterious inflammatory reaction, and work to maintain the defense mechanisms at their due levels.

*Experimental Neuropathology Unit, Institut Pasteur, Paris, France

4th Department of Internal Medicine, National and Kapodistrian University of Athens, Medical School, Athens, Greece

Address reprint requests to Jean-Marc Cavaillon, Dr.Sc., Experimental Neuropathology Unit, Institut Pasteur, 28 rue Dr. Roux, 75015 Paris, France. E-mail: jean-marc.cavaillon@pasteur.fr

Received 6 July, 2018

Revised 24 July, 2018

Accepted 13 September, 2018

The authors report no conflicts of interest.

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INTRODUCTION

The words immunoparalysis (1), immunodepression (2), or anergy (3) have been commonly used to qualify the immune status of patients with sepsis or systemic inflammatory response syndrome (SIRS). More recently, the word immunosuppression has become the most popular term to capture the modified properties of the circulating immune cells following trauma (4), surgery (5), hemorrhage (6), burns (7), and sepsis (8). Not only are these words not appropriate, they are misleading. They suggest that an immune failure would influence the outcome of patients similar to as in organ failure. The concept of immunosuppression emerged when it was realized that the inflammatory response was accompanied by a counterinflammatory response aimed at dampening overzealous inflammation (9). The side effect of this regulatory mechanism is an alteration of the immune status. Posttraumatic immunosuppression has been claimed to be the one of leading causes of postsurgical mortality (10), and reversing immunosuppression has been proposed as a potentially major advance in the treatment of sepsis (11). As we will review, this alteration is neither a global deficiency of the immune response nor a systemic process. To better reflect the reality, we favored the concept of leukocyte reprogramming to qualify the events associated with the anti-inflammatory response (12).

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SYSTEMIC INFLAMMATORY RESPONSE SYNDROME, COMPENSATORY ANTI-INFLAMMATORY RESPONSE SYNDROME, AND PERSISTENT INFLAMMATION, IMMUNOSUPRESSION, AND CATABOLISM SYNDROME

In 1992, sepsis was defined as the systemic inflammatory response syndrome (SIRS) associated with a severe infectious process (13). SIRS is accompanied by a cytokine storm that may lead to multiple organ failure (MOF). Five years later Bone et al. proposed a new acronym, CARS (compensatory anti-inflammatory response syndrome), to qualify the consequences of the anti-inflammatory process aimed at stopping the inflammatory reaction. In the initial definition it was considered that either SIRS or CARS were predominating within patients, ending in either organ dysfunction and cardiovascular compromised shock or in the suppression of the immune system, respectively (14). However, another acronym, MARS, for mixed antagonist response syndrome was also coined to characterize the features of SIRS in patients with CARS. In revisiting this concept, SIRS and CARS were considered to be always occurring concomitant. We proposed that CARS should be rather considered as an adapted compartmentalized response with the aim to silence some acute proinflammatory genes, and to maintain the possible expression of certain genes involved in the anti-infectious process (15). In our previous review, we listed the cell surface markers, and functions of monocytes and neutrophils that were either enhanced or reduced illustrating that CARS is not a complete shutdown of all leukocyte parameters. A new and interesting acronym was proposed in 2012. PICS, for persistent inflammatory, immunosuppressed, catabolic syndrome (16), characterizes the clinical setting of patients who survived the first hit, and who stay in the intensive care unit (ICU) for more than 10 days. These ICU long-term surviving patients display simultaneously features of inflammation, altered immune status, and catabolic syndrome. In 2016, a new definition of sepsis was proposed: sepsis now becoming “a life-threatening organ dysfunction caused by a dysregulated host response to infection” (17). Accordingly, the experts consider that the innate immunity (the host response to infection) of individuals dealing with a severe infection is abnormal, impaired, or failing (cf. definition of the word “dysregulation”). This is a rather surprising view because perfectly healthy people can develop sepsis, suggesting that sepsis can occur in patients with a normal immune system. Probably, the most appropriate descriptor is “maladaptive” because it is the intensity of the host response which can be deleterious leading to organ dysfunction and to a modification of the immune system. An altered immune status is regularly associated with an increased frequency of nosocomial infections among ICU patients. Particularly, viral reactivation (cytomegalovirus, herpes simplex virus, Epstein-Barr virus, etc.) has been reported in influencing the length of hospital stay, disease severity, and eventually outcome (18–24). However, evidence supporting nosocomial infection as the major cause of death in sepsis remains weak (25). Indeed, the overall contribution of secondary infections in short-term mortality was shown in a Dutch investigation to be quite modest (26). As stated by Derek Angus and Steven Opal, “Early hopes that immune suppression would be a unifying and common feature of all patients with sepsis who have poor outcomes are not supported by this study. However, immune dysfunction does appear to have an important role in a subset of patients” (27). Most interestingly, in a study of solid organ transplant patients, recipients with sepsis had a significantly lower risk of death at 28 days than nontransplanted patients (28). This study suggested that the immunosuppression associated with transplantation may rather provide a survival advantage to the transplant recipients with sepsis through the modulation of the inflammatory response.

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PARAMETERS USED TO MONITOR THE ALTERED IMMUNE STATUS

In vivo skin test reaction

In the mid-1970s, a Canadian team revealed that delayed-type hypersensitivity assessed by skin test reactivity to five antigens could be altered in 50% of tested critically ill patients (most with sepsis) (29) (Fig. 1). A total or partial anergy associated with poor outcome was reported by some authors (30, 31), but not by others (32). The skin test anergy was associated with a deficiency in neutrophil chemotaxis (33).

Fig. 1

Fig. 1

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Lymphopenia

Lymphopenia is regularly reported in septic patients. It affects B-lymphocytes, as well as NK cells, and CD4+ and CD8+ T-lymphocytes (34, 35). Only the number of regulatory T-cells (Treg) appears to be maintained (36). A decreased number of dendritic cells has also been reported (37). A meta-analysis on 9 studies (992 patients) suggests that the reduction of circulating B-cell at the onset of sepsis is associated with decreased survival (38). These reduced numbers of circulating cells can be mimicked by the administration of living bacteria, endotoxin (lipopolysaccharide [LPS]), interleukin-1 (IL-1), or tumor necrosis factor-α (TNFα). The decrease in cells may reflect the trapping of circulating lymphocytes within lymphatic tissues and organs, as well as an increase in apoptosis. Another parameter that contributes to lymphopenia is the ablation of osteoblast during sepsis, due to osteoblasts contributing to the production of IL-7, the main lymphopoietic cytokine (39).

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Apoptosis

An increased number of apoptotic circulating lymphocytes has been reported in septic shock patients (40). Of note, during sepsis and SIRS, apoptosis also occurs in epithelial cells, endothelial cells, cardiac myocytes, neurons (41), and to a lesser degree muscle cells (42). In contrast, spontaneous and induced apoptosis of neutrophils is reduced (43–45). Most interestingly, apoptosis of lymphocytes and dendritic cells was reported in the spleen of patients who did not survive sepsis (46) and targeting apoptosis has been regularly reported by Richard Hotchkiss’ team as a beneficial approach in experimental models of sepsis (47, 48). Compellingly, a link between apoptosis of immune cells and the altered delayed-type hypersensitivity was reported to occur after the release of TNF-related apoptosis-inducing ligand (TRAIL) by CD8+ regulatory T-lymphocytes (49). In contrast, no major apoptosis of monocytes has ever been observed (50).

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HLA-DR expression

In 1990, Hershman et al. (51) first reported a decreased frequency in HLA-DR+ monocytes soon after the occurrence of trauma in healthy individuals. They showed that a slow improvement was observed in uneventful recovery, whereas a decrease was maintained in patients who develop sepsis and was even further pronounced in patients who ultimately died. In patients with sepsis, or with an ruptured abdominal aortic aneurysms, whereas the level of expression at admission was not predictive of outcome, measurement made on day 3 was discriminant in distinguishing those who would survive from those who would not (52, 53). In burns, trauma, and intensive care patients, the levels of HLA-DR can also be predictive of the occurrence of sepsis (54–56). Many other cell surface markers are either decreased (TNF Receptor p75, CD14, Toll-like receptor 4 [[TLR4], transferrin receptor [CD71], co-activation marker [CD86], and fractalkine receptor [CX3CR1]) or increased (TNF receptor p50, CD40, CD48, CD64, CD69, Triggering receptor expressed on myeloid cells-1 [TREM-1], tissue factor, programmed death-1 [PD1], and PD-Ligand-1 [PDL1]) on monocytes (15).

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Lymphocyte proliferation

In animal models, late after an insult (i.e., ≥ 96 h), the lymphocyte proliferative response to mitogens was decreased (57, 58). Similarly, in septic shock patients a significant reduced capacity of circulating lymphocytes has been reported in response to phytohemagglutinin, pokeweed mitogen, and concanavalin A (59). In this later observation, Venet and colleagues assigned Tregs as the culprits.

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Ex vivo cytokine production

Upon ex vivo activation by LPS, circulating monocytes from septic and SIRS patients display a lower capacity to release IL-1α, IL-1β, IL-6, and TNFα compared with healthy subjects (60). This is associated with significant risk for an unfavorable outcome and persists until day 10 (61). LPS-activated neutrophils release lower levels of IL-1 and IL-8 (62, 63), and NK cells in response to LPS added, to the appropriate cytokine cocktail, release lower levels of gamma-interferon (IFNγ) (64). In response to appropriate antibodies (anti-CD3 and/or anti-CD28 and/or anti-CD4) or mitogens, T-lymphocytes also display a reduced capacity to release Th1 and Th2 cytokines (65, 66). Animal models of sepsis and SIRS revealed similar altered capacity of T-lymphocytes to produce cytokines upon activation. The altered function of accessory cells can in itself influence the suppression of T-cell function. Notably, a major influence of sex has been regularly reported by Chaudry's group (67). In contrast to a decrease capacity in releasing cytokines, ex vivo IL-10 production has repeatedly been shown to be enhanced (40, 65–71).

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Metabolic defects

There is a generalized metabolic defect at the level of both glycolysis and oxidative metabolism in leukocytes from septic patients. Severe defects in human leukocyte energy metabolism, as seen in a shift from oxidative phosphorylation to aerobic glycolysis, have been shown to be reversed by IFNγ immunotherapy (72). As shown in murine models, the energy substrate changed depending on the degree of sepsis (73). The pentose phosphate pathway is upregulated during acute hyperinflammatory responses, whereas the β-oxidation of fatty acids is increased at a later stage during sepsis (74).

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An individualized process

We completed a study to measure, through flow cytometry, the innate and adaptive immune statuses within the first 24 h from the onset of the first sign of SIRS. A total of 505 patients were classified according to severity and infection site (75). Surprisingly, it was found that when compared with less severe patients, a decrease of the expression of HLA-DR on CD14-monocytes was found only in patients suffering from acute pyelonephritis and intraabdominal sepsis; however, CD4- and CD8-lymphopenia were only noted in severe sepsis/septic shock, developing after a community-acquired pneumonia and intra-abdominal infection. Finally, B-lymphopenia was shown only in severe sepsis/septic shock developing after community-acquired pneumonia. Thus, the nature of the bacterial infection, its origin (community or nosocomial), its site, and its severity exert different pressures on the immune system. This study illustrates the heterogeneity of patients with sepsis and points out that numerous key parameters of severe infection influence the immune status.

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WHEN DOES IT OCCUR?

For more than a decade (2001–2013), authors have regularly published figures in which they showed that soon after the insult, the activation of the proinflammatory response (SIRS) was induced followed later by the anti-inflammatory response (CARS) (76–78). However, as early as 1995, three papers where published showing that plasma levels of IL-10 correlated with the levels of inflammatory cytokines, illustrating that both the proinflammatory and the anti-inflammatory phases were concomitant (79–81). In 2001, we published a figure illustrating that SIRS and CARS were occurring almost concomitantly, a concept widely accepted nowadays (82). We suggested that SIRS was predominating within the inflamed tissues, whereas CARS was mainly affecting the circulating leukocytes. Since then, papers have confirmed that the arbitrary distinction of separating sepsis into proinflammatory and anti-inflammatory phases was not supported by plasma cytokine measurements (83), by gene-expression data (84), nor by assessing the immune status of septic patients (85). Many examples illustrate the rapid occurrence of the modification of the immune status of circulating leukocytes, particularly in clinical settings when time zero, i.e., the initiation of the insult, is known. In surgery, blood samples harvested during surgery within the operating room display reduced ex vivo cytokine production (86), and HLA-DR expression on monocyte is lowered (87). A few hours after trauma (88) or in resuscitated patients after a cardiac arrest (89), the ex vivo LPS-activation leads to a lower production of inflammatory cytokines as compared with the healthy controls. Most impressive was the study of trauma patients whose blood was sampled at the scene of the trauma (69). Peter Pickkers’ team revealed that soon after the accident, circulating danger-associated molecular patterns (DAMPs) could be detected; leukocyte HLA-DR mRNA expression and proinflammatory cytokine production assessed in ex vivo whole blood assays in response to LPS stimulation were reduced. Studying the transcriptomics of circulating leukocytes in critically ill patients, Xiao et al. (90) concluded that a rapid induction of innate immunity genes occurs simultaneously with the suppression of adaptive immunity genes.

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THE INTENSITY OF THE REPROGRAMMING IS A REFLECTION OF THE SEVERITY OF THE INSULT

The downregulation of the parameters used to monitor the immune status (mostly ex vivo cytokine production and monocyte expression of HLA-DR) is pronounced the most in the most severe patients as illustrated by the negative correlation between the immune status and the severity score used in sepsis, severe multiple injury, or burns (e.g., SOFA, ISS, MODS, ABSI) (55, 88, 91–93). The lowest values measured were among the patients who ultimately died (51, 52, 94), and in those whose values failed to recover to normal baselines (60). Because the intensity of the altered immune status parameters reflects the severity of the insult, and because the severity of the insult is associated with the occurrence of nosocomial infection, the intensity of the reprogramming is also associated with the number of days under ventilation (95), the occurrence of adverse clinical conditions (96), and the occurrence of nosocomial infections (92). Most interestingly, the link between poor outcome and the intensity of the immune status alteration has been similarly observed within the murine cecal ligation and puncture (CLP) sepsis model when compared with the immune status of mice predicted to die versus mice predicted to survive (a prediction made according to the levels of circulating IL-6) (97). Thus, the intensity of the immune status alteration reflects the severity of the insult and correlates with clinical scores or markers of severity such as ferritin or IL-6. Accordingly, whether immunomonitoring is needed to offer personalized medicine is questionable.

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FROM ENDOTOXIN TOLERANCE TO LEUKOCYTE REPROGRAMMING

The observations made in septic and SIRS patients are reminiscent of the endotoxin tolerance phenomenon initially described by Paul Beeson in 1946 (98). Currently, characterized as the reduced production of cytokines, such as TNFα, observed in vivo(99) or in vitro(100) after a second encounter with an endotoxin soon after an initial injection/stimulation, the tolerance to endotoxins shares many similarities with the phenomena seen in septic and SIRS patients (101). When in 1995, we claimed that this phenomenon was not specific to endotoxins, this concept was not yet well recognized (102). Nowadays, a cross-tolerance between pathogen-associated molecular patterns (PAMPs) and DAMPs is well recognized (103). In 1993, Zhang and Morrison used the word “reprogramming” to characterize the endotoxin tolerance phenomenon (104). This word appeared fully appropriate when Medzhitov's team (105) showed that endotoxin tolerance does not correspond to a global anergy, but to epigenetic modifications ending in tolerizable and nontolerizable genes. Accordingly, not all of the functions of monocytes/macrophages are reduced. Several studies have shown that tolerized macrophages display enhanced phagocytosis (106–108), enhanced generation of free radicals (109), and enhanced expression of certain genes, including lipocalin-2, S100A8, S100A9, and IL-10 (110, 111). As discussed below, the word “reprogramming” fully defines the exact status of the circulating immune system in septic and SIRS patients (12). Interestingly, it was reported that in septic patients the alteration of the ex vivo release of TNFα from circulating monocytes was related with the extent of endotoxemia (112). Most fascinatingly, it was the report by Pena et al. (113), studying the transcriptomics of circulating leukocytes, that in septic patients there is an “endotoxin tolerance signature” which was strongly associated with the severity of the disease as assessed by organ failure. However, in sharp contrast to the concept that the modification of the immune status of critically ill patients may favor the occurrence of nosocomial infections, endotoxin tolerance allows for an increased resistance to fungal (114), bacterial (115, 116), polymicrobial (117–119), viral (120), and parasitic infections (121). Of note, the old concept of tolerance to endotoxins and any TLR ligands, requalified as reprogramming, has been recently revisited, leading to the proposition of the concept of “trained innate immunity” (122). A consensus on appropriate terminology is still needed. Currently, subtle differences may exist depending on the initial stimuli, which can either tolerize or prime the immune cells (123).

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WHAT ARE THE UNDERLYING MOLECULAR MECHANISMS?

Inflammatory plasma: an immunosuppressive milieu

During sepsis and SIRS, circulating leukocytes are bathing in an immunosuppressive milieu (124). The presence of immunosuppressive factors in the plasma or the sera was reported from the beginning when an observed altered immune status in terms to an anergy to skin test antigens was investigated (29). The addition of a patient's sera onto leukocytes from healthy controls ended in impairment of mitochondrial respiration (128) and in the reduction of TNF and IL-6 production (125), expression of HLA-DR on monocytes after an intracellular sequestration of the surface marker (126), intracellular calcium signaling by peripheral blood mononuclear cells (127), and the expression of CD24 in neutrophils (45), and an impaired mitochondrial respiration (128). The regulatory properties of plasma from septic patients can act on cells types other than leukocytes. Impaired function of hepatocytes has been reported when those cells were exposed to septic plasma (129). Many factors present in SIRS or sepsis plasma may contribute to this immunosuppressive environment. These include IL-10 (125, 126, 130, 131), IL-33 (132), transforming growth factor-β (TGFβ) (133–135), prostaglandin E2 (PGE2) (136, 137), nitric oxide (NO) (138, 139), lactate (140, 141), cortisol (87), and the chemokine CCL2 (142). Apoptotic T-cells (134), regulatory T-cells (135, 143, 144), myeloid-derived suppressor cells (145, 146), and bone marrow stroma cells (147) contribute to this molecular immunosuppressive environment. Paradoxically, their contribution has been regularly reported to be protective (147–149).

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Intracellular mechanisms

Reprogramming of macrophages after a first hit implies the involvement of cell surface markers, intracellular negative signaling molecules, negative regulation on gene promoters, epigenetic regulation, and miRNAs (150, 151) (Fig. 2). These events occur after cell activation and are in response to negative exogenous mediators such as anti-inflammatory cytokines (IL-10, IL-35, IL-37, IFNα, and TGFβ), acetylcholine, lipid specialized proresolving mediators (lipoxins, resolvins, maresins, and protectins), and a cross-talk with regulatory T-cell via the PD1/PDL1 interaction. Negative intracellular regulators such as MyD88s (152), IRAK-M (153, 154), and ABIN-3 (155) have been reported to be upregulated in cells from septic or SIRS patients, and modification of the ratio of the active versus the inactive form of NF-κB has also been reported (156, 157). From the surface, negative signals can be delivered by TLR10, SIGIRR, Tim-3, or ST2. CD39 can catabolize the ATP that is needed for IL-1β and IL-18 release. Interestingly, certain specialized proresolving mediators can favor the expression of certain negative regulators, such as A20 and SIGIRR, which limit NF-κB activation (158). The complexes glucocorticoid/glucorticoid receptor and aryl hydrocarbon receptor (AHR)/AHR nuclear translocator act directly on gene promoters, although numerous epigenetic modifications are occurring (159, 160). In addition, miRNAs contribute to negative signaling events (161). Finally, a decrease in mitochondrial activity and oxidative phosphorylation, leading to reduced cellular metabolism, has been noted (162). This process has been considered by Mervyn Singer as a mitochondrial hibernation (163).

Fig. 2

Fig. 2

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IT IS NOT A GLOBAL DEFECT

Many years ago, we claimed that the alteration of the immune status as assessed via ex vivo cytokine production observed in sepsis and SIRS was not a global defect (82). Later on, we listed the cell surface markers that are either downregulated or upregulated on the membrane of monocytes and neutrophils during sepsis and SIRS (15). Since our report, new studies have further illustrated that the cells are not globally immunosuppressed, but are reprogrammed. For example, in patients with stroke-related brain death we have shown that in whole blood assays the ex vivo TNF production by monocytes in response to LPS was decreased when compared with healthy subjects. Meanwhile, the response to whole bacteria (Escherichia coli or Staphyloccocus aureus) was unaltered, whereas the production of IL-10 was enhanced independently of the agonists when compared with the control (42). A similar increase in IL-10 production was reported in B-lymphocytes in response to ex vivo stimulation (164). An injection of LPS into human volunteers ended in a reduction of IL-2, IFNγ, and IL-17 production by T-cell subsets in response to PMA + ionomycin, but the production of IL-10 was unaltered (165). In a study analyzing the reactivity of circulating dendritic cells in terms of IL-12 production in response to various TLR agonists, Asehnoune's team reported that the responses to TLR3 and TLR4 agonists were significantly decreased as compared with healthy controls, but the response to a TLR7/8 agonist was unchanged (166). In patients with sepsis, it was reported that monocyte-dependent indoleamine 2,3-dioxygenase activity was reduced in response to LPS, but was unchanged in response to IFNγ (167). Most interestingly, in a murine model of hemorrhagic shock, Asehnoune et al. (168) showed that the ex vivo production of TNF in response to LPS was altered, although that was not the case in response to heat-killed S. aureus. These results further illustrate that the nature of the activator used to stimulate the cells greatly influenced the read out. The most convincing proof of this was provided by Biswas’ team. They showed during sepsis that the monocytes display enhanced phagocytosis, enhanced anti-microbial activity, enhanced metalloproteinase-9 and -19 mRNA production, and enhanced VEGFα release when compared with monocytes of septic patients after recovery (154). Recent investigations on T-cells from septic patients studying their activation via the T-cell receptor concluded that the T-cells exhibit a primed phenotype, arguing against the notion of a generalized paralysis of T-cells (169).

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IT IS NOT A SYSTEMIC PHENOMENON: COMPARTMENTALIZATION

In previous reviews we addressed the concept of compartmentalization as an important parameter to take into consideration when looking at a global, appropriate, view of the consequences of a severe inflammatory reaction (103, 170). In one of these reviews we recalled the legend of the elephant and the blind men to illustrate that the analysis is greatly influenced depending where it is made. In endotoxin tolerance models, it was reported that alveolar macrophages do not undergo tolerization because of their specific microenvironment and the local influence of B-lymphocytes, NK cells, GM-CSF, IFNγ, and IL-18 (171). Most importantly, this observation was confirmed in human volunteers (172, 173), and in patients with acute respiratory distress syndrome, spontaneous and LPS-induced IL-1 productions were enhanced when compared with healthy subjects (174). When signaling molecules were studied in neutrophils from a hemorrhage murine model or after LPS administration, activation was observed in the cells derived from the lungs but not in the cells derived from the blood (175, 176). In murine in vivo models, it was demonstrated that endotoxin tolerance illustrated by a decreased detection of TNF in the blood stream was in contrast associated with an increased TNF production within the renal cortex (177). One of the most convincing demonstration was reported by Chaudry's group when analyzing the murine model of peritonitis alone or associated with trauma–hemorrhage (178). They showed that the ex vivo production of TNF in response to LPS was reduced among peripheral blood mononuclear cells and spleen cells, whereas the production by alveolar macrophages and liver Kupffer cells was enhanced. In the murine model of sepsis, it was reported that spontaneous IL-12 production was reduced when analyzing splenic dendritic cells, whereas in peritoneal dendritic cells it was enhanced (179). Similarly, in human peritonitis, LPS + IFNγ induced more IL-1 production in peritoneal macrophages when compared with infection-free donors (180). In the skin, it was demonstrated that resident memory CD8+ T-lymphocytes maintain Ag-dependent “sensing and alarming” function (assessed in terms of IFNγ production) after sepsis in contrast to the reduced activity seen in spleen CD8+ T-lymphocytes (181). An important question was recently addressed concerning microglial cells. In a murine model of sepsis it was reported that ex vivo activation of isolated microglial cells was associated with an increase in TNF release in response to LPS when compared with control animals (182). This later result is reminiscent of the long-lasting detection of TNF after a LPS injection (183) and the nuclear NF-κB upregulation in the hypothalamus of rat injected with repeated doses of LPS (184). Although adipose tissues contribute to inflammatory cytokine production upon LPS injection or after sepsis (185, 186), their involvement seems to increase with age (187). To our knowledge, the nature of the reprogramming within these tissues has been poorly studied so far. Another compartment in which an ongoing activation process has been regularly reported in sepsis is in bone marrow. Indeed, hemophagocytosis has been regularly found in 60% to 65% of septic and SIRS patients (188–190). High levels of ferritin has been proposed as a marker of poor outcome and for macrophage activation like syndrome, although its frequency remains below of those reported after direct bone marrow cell analysis (191).

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THE ALTERATION OF THE IMMUNE STATUS IS REVERSIBLE

Different types of immune-modulation have been shown to help circulating cells recover their immune status. In 1997, IFNγ was successfully used in septic patients to aid the recovery of HLA DR expression and ex vivo TNF production (192). The same team in Berlin used GM-CSF with similar efficacy (193). Monneret's team, in Lyon, showed that IL-7 could restore the lymphocyte's immune function (194), whereas the in vivo treatment counteracts the T-cell lymphopenia (195). The use of other cytokines such as IL-15 (196) and IL-12 (197) has been put forward. Of particular interest was the extracorporal activation of circulating leukocytes by IL-2 in a study that ended with an improved outcome for septic patients (198). Such an approach has the advantage to target circulating cells, preventing the treatment from reaching immune cells within tissues which are not deactivated (41). Blocking β2-adrenoceptor has been shown to protect and/or to restore the immune status in different inflammatory models such as hemorrhage (168) and stroke (199). Targeting PD1 or PDL-1 has also been shown to restore monocyte function and to improve mortality (200).

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CONCLUSION

Despite the worldwide use of the word immunosuppression to qualify the immune status of SIRS and septic patients, we consider that this represents an oversimplification of the process that is occurring in immune cells. Although many parameters are indeed associated with an altered immunity, a more careful analysis reveals that the nature of the agonists used to investigate the cell reactivity influences the results; that different cellular functions can be reduced, unchanged, or even enhanced; and that the location of the immune cells greatly influences their functional status. As a consequence, the immune status of leukocytes reflects an adapted compartmentalized appropriate response aimed to prevent an overzealous inflammatory reaction and to maintain an anti-infectious process. Instead of immunosuppression, the word “reprogramming” better reflects the immune status of circulating leukocytes in SIRS and septic patients.

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Keywords:

Lymphocytes; macrophages; monocytes; neutrophils; sepsis; tolerance; trained immunity

© 2019 by the Shock Society