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      Using the Extremes of Human Inflammation to Understand the Transcriptional Control of IL-18

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          Abstract

          Hemophagocytic lymphohistiocytosis (HLH) is a rare pediatric syndrome associated with inherited defects in the expression or extracellular secretion of perforin, a pore-forming protein expressed by cytotoxic CD8 T cells or natural killer cells (1). Impairments in perforin function prevent these cytolytic cells from inducing apoptosis in virally infected (or otherwise damaged) host cells, leading to a persistent nidus of innate immune activation. The consequent “cytokine storm” of HLH manifests as a febrile illness with features of multiorgan dysfunction, such as hepatitis, splenomegaly, cytopenia (especially anemia and thrombocytopenia), and central nervous system dysfunction (2). Histology of affected tissues reveals expansion of aberrantly activated T cells and macrophages that phagocytose host myeloid and erythroid cells. A diagnosis of HLH is catastrophic, with a >90% mortality at a young age in the absence of chemotherapeutics or bone marrow transplantation (3). Although primary HLH is rare, there is increasing recognition of secondary forms of HLH (sHLH), characterized by an acquired loss of cytolytic cell function (1, 4, 5). One variant of sHLH is macrophage activation syndrome (MAS), a feared complication of pediatric rheumatologic diseases such as systemic juvenile idiopathic arthritis (sJIA) (6). Although the etiology of MAS is complex, emerging studies indicate that the chronic inflammatory activation of autoinflammatory diseases such as sJIA suppresses cytolytic cell function, potentially leading to an unremitting inflammatory response to virally infected cells (1, 6, 7). Persistent induction of macrophage activation leads to hemophagocytosis and the release of numerous proinflammatory cytokines (7, 8), mimicking the clinical findings of primary HLH. Given that many adult patients suffer from chronic inflammatory diseases, there is increasing concern that these patients may develop MAS-like disease states when hospitalized for acute insults such as infection or malignancy (9). As such, MAS may be underrecognized in adult ICUs. There is accordingly a need to mechanistically understand the proinflammatory pathways responsible for not only the onset of sHLH/MAS but also the consequent multisystemic organ injury responsible for disease morbidity and mortality. In this issue of the Journal, Verweyen and colleagues (pp. 526–539) investigate the role of IL-18 in the pathogenesis of MAS (10). IL-18 is a member of the IL-1 cytokine family, which includes IL-1β. Similar to IL-1β, IL-18 is transcribed and translated as a propeptide and then cleaved into an active form by caspases. As therapeutic inhibition of IL-1β yielded only mixed benefits in the treatment of MAS, there is increasing interest in the role of IL-18 as a potential therapeutically targetable mediator of this disease state (1). Intriguingly, Verweyen and colleagues establish the scientific premise for their investigations of MAS by studying IL-18 in a disease state at the opposite end of the inflammatory spectrum: postseptic immunoparalysis. Healthy human volunteers exposed to two sequential doses of intravenous LPS developed endotoxin tolerance, characterized by suppressed TNFα (tumor necrosis factor α), IL-6, and IL-1β release into the circulation after the second LPS exposure (11). Endotoxin tolerance was similarly induced ex vivo by sequential dosing of healthy human peripheral blood monocytes with LPS. In these in vivo human and ex vivo monocyte studies, the authors observed that IL-18 escaped endotoxin tolerance, contrasting the suppression of tumor necrosis factor α, IL-6, and IL-1β. The authors suggest that this escape from endotoxin tolerance may be a consequence of a uniquely delayed induction of IL-18 transcription after LPS. Although transcription of other cytokines peaked and resolved rapidly after the first LPS dose, the delayed kinetics of IL-18 transcription led to ample IL-18 mRNA availability at the time of the second LPS dose, potentially providing continued substrate for protein translation. The authors speculate that these unique IL-18 kinetics, which corroborate a recently published study of IL-18 and IL-1β by Zhu and Kanneganti (12), allow for persistent expression of an inflammatory cytokine that escapes LPS tolerance, a finding potentially relevant to unremitting auto-inflammatory states such as MAS. After identifying delayed transcription of IL-18 after LPS, the authors sought to determine the factors responsible for these unique transcriptional kinetics. Using human peripheral blood monocytes, the authors observed that IL-18 induction was maximal after TLR4 (Toll-like receptor 4) activation, with TLR5 agonists inducing only a blunted activation of IL-18. In addition to TLR agonism, induction of IL-18 transcription required type I IFN (IFN α/β) activation of JAK/STAT signaling. Conversely, type II IFN (IFN γ) had no effect on IL-18 transcription. Type I IFN not only induced IL-18 but also controlled the kinetics of translation: pretreatment of monocytes with IFN α/β accelerated the onset of LPS-induced IL-18 transcription. These findings were confirmed using peripheral blood monocytes collected from a patient with a STAT1 gain-of-function mutation. Notably, the authors did not test whether this acceleration of IL-18 transcription reversed the previously observed ability of IL-18 to escape endotoxin tolerance. Interestingly, type I IFN/JAK/STAT signaling had an opposite, inhibitory effect on IL-1β expression in normal human peripheral blood monocytes, again demonstrating divergent mechanisms of transcriptional control of these related cytokines (12). After using models of endotoxin tolerance to identify the unique transcriptional kinetics of IL-18, Verweyen and colleagues shifted their focus to investigate the effect of type I IFN/JAK/STAT/IL-18 signaling on auto-inflammatory diseases such as sJIA and MAS. In patients with sJIA or other autoinflammatory states (e.g., familial Mediterranean fever [FMF]), peripheral blood monocyte expression of IL-18 was highly correlated with expression of IFN-related genes, suggesting a mechanistic association. Furthermore, microtubule destabilizing agents such as colchicine or nocodazole, commonly used to treat autoinflammatory diseases, suppressed IL-18 and IFN β expression in LPS-treated peripheral blood monocytes. Colchicine- or nocodazole-induced suppression of IL-18 transcription could be reversed by the administration of exogenous IFN α/β. The translational relevance of these findings was supported by an observed suppression of circulating IL-18 in colchicine-treated patients with FMF. Finally, the authors confirmed the importance of JAK/STAT signaling to IL-18 expression in vivo by analyzing samples collected from previously published studies of mouse models of MAS (13, 14). These models, in which a MAS-like phenotype is induced by repeated dosing with the TLR9 agonist CpG (with concurrent hemophagocytosis, if IL 10 is additionally inhibited [1]), revealed that treatment with the JAK1/2 inhibitor ruxolitinib suppressed IL-18 expression. Furthermore, treatment of a MAS human patient, who experienced a partial response to anti-IL-18 therapy (15), with the JAK1/3 inhibitor tofacitinib similarly suppressed circulating IL-18, coincident with improved clinical outcomes. Taken together, this comprehensive work by Verweyen and colleagues elegantly used pathologic extremes of human inflammation, ranging from postseptic immunoparalysis to fulminant autoinflammatory disorders such as MAS and FMF, to glean new insights into the transcriptional control of IL-18. Similar to most important studies, there remain numerous unanswered questions. In contrast to IFN α/β signaling, the authors found that IFN γ, a cytokine with known importance to MAS pathogenesis (1), exerted minimal impact on IL-18 signaling. These findings demonstrate that the complex pathophysiology of these autoinflammatory conditions likely cannot be explained by IL-18 alone. Furthermore, it is uncertain if (and how) the authors’ work, derived largely from ex vivo studies of LPS-treated peripheral blood monocytes, can be extrapolated to inform the in vivo behavior of CD8 T cells and/or hemophagocytic tissue-resident macrophages pathognomonic of MAS. Nevertheless, this work provides exciting insights into the mechanisms responsible for control of IL-18 expression while identifying therapeutic targets (e.g., type I IFN, JAK/STAT signaling) that may potentially help patients with autoinflammatory disease.

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          Most cited references10

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          Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study.

          Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.
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            Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome

            Publisher's Note: There is a [Related article:] Blood Commentary on this article in this issue. IL-18 distinguishes susceptibility to MAS amongst hyperferritinemic and autoinflammatory diseases. Excess IL-18 in NLRC4 gain-of-function mice derives from intestinal epithelia, and free IL-18 promotes experimental MAS. Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperferritinemic systemic inflammatory disorders. Although profound cytotoxic impairment causes familial HLH (fHLH), the mechanisms driving non-fHLH and MAS are largely unknown. MAS occurs in patients with suspected rheumatic disease, but the mechanistic basis for its distinction is unclear. Recently, a syndrome of recurrent MAS with infantile enterocolitis caused by NLRC4 inflammasome hyperactivity highlighted the potential importance of interleukin-18 (IL-18). We tested this association in hyperferritinemic and autoinflammatory patients and found a dramatic correlation of MAS risk with chronic (sometimes lifelong) elevation of mature IL-18, particularly with IL-18 unbound by IL-18 binding protein, or free IL-18. In a mouse engineered to carry a disease-causing germ line NLRC4 T337S mutation, we observed inflammasome-dependent, chronic IL-18 elevation. Surprisingly, this NLRC4 T337S -induced systemic IL-18 elevation derived entirely from intestinal epithelia. NLRC4 T337S intestines were histologically normal but showed increased epithelial turnover and upregulation of interferon-γ–induced genes. Assessing cellular and tissue expression, classical inflammasome components such as Il1b , Nlrp3, and Mefv predominated in neutrophils, whereas Nlrc4 and Il18 were distinctly epithelial. Demonstrating the importance of free IL-18, Il18 transgenic mice exhibited free IL-18 elevation and more severe experimental MAS. NLRC4 T337S mice, whose free IL-18 levels were normal, did not. Thus, we describe a unique connection between MAS risk and chronic IL-18, identify epithelial inflammasome hyperactivity as a potential source, and demonstrate the pathogenicity of free IL-18. These data suggest an IL-18–driven pathway, complementary to the cytotoxic impairment of fHLH, with potential as a distinguishing biomarker and therapeutic target in MAS.
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              Reactive hemophagocytic syndrome in adults: a retrospective analysis of 162 patients.

              Current knowledge in reactive hemophagocytic syndrome mainly relies on single-center case series including a relatively small number of patients. We aimed to identify a multicenter large cohort of adult patients with reactive hemophagocytic syndrome and to describe relevant clinical and laboratory features, underlying conditions, and outcome.
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                Author and article information

                Journal
                Am J Respir Crit Care Med
                Am. J. Respir. Crit. Care Med
                ajrccm
                American Journal of Respiratory and Critical Care Medicine
                American Thoracic Society
                1073-449X
                1535-4970
                1 March 2020
                1 March 2020
                1 March 2020
                1 March 2020
                : 201
                : 5
                : 503-504
                Affiliations
                [ 1 ]Department of Medicine
                [ 2 ]Department of Pharmacology

                University of Colorado Denver Anschutz Medical Campus

                Aurora, Colorado

                and
                [ 3 ]Department of Medicine

                Denver Health Medical Center

                Denver, Colorado
                Author information
                http://orcid.org/0000-0002-7360-0504
                Article
                201912-2322ED
                10.1164/rccm.201912-2322ED
                7047457
                31898912
                591c5615-38e7-466f-9ebc-cbeb08aa576b
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

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