IL‐37 is a unique member of the IL‐1 family of cytokines, which functions as a natural suppressor of inflammatory and immune responses. Immune and non‐immune cells produce IL‐37 precursor following ...pro‐inflammatory stimuli. Following activating cleavage by caspase‐1, mature IL‐37 translocates to the nucleus, where it suppresses transcription of pro‐inflammatory genes. Both precursor and mature IL‐37 are also secreted in the extracellular space, where they bind IL‐18Rα and recruit the IL‐1R8 (formerly TIR8 or SIGIRR), which transduces anti‐inflammatory signals by suppressing NF‐kB and MAPK and by activating Mer‐PTEN‐DOK pathways. During inflammation, IL‐37 restores the metabolism of the cell by reducing succinate, inhibiting mTOR, and activating AMPK. Transgenic mice expressing human IL‐37 and wild type mice treated with recombinant human IL‐37 are protected from several experimental models of inflammation, including endotoxin shock, colitis, lung and spinal cord injury, coronary artery disease, arthritis and inflammation‐induced fatigue, while also exhibiting reduced adaptive immune responses. In humans, IL‐37 likely functions to limit excessive inflammation: accordingly, IL‐37 levels are abnormal in patients with inflammatory and autoimmune diseases. In this review, we provide an overview of the discovery and biology of IL‐37, and discuss the potential for development of this cytokine as a therapeutic agent.
Interleukin-1 (IL-1) is the prototypical inflammatory cytokine: two distinct ligands (IL-1α and IL-1β) bind the IL-1 type 1 receptor (IL-1R1) and induce a myriad of secondary inflammatory mediators, ...including prostaglandins, cytokines, and chemokines. IL-1α is constitutively present in endothelial and epithelial cells, whereas IL-1β is inducible in myeloid cells and released following cleavage by caspase-1. Over the past 30 years, IL-1-mediated inflammation has been established in a broad spectrum of diseases, ranging from rare autoinflammatory diseases to common conditions such as gout and rheumatoid arthritis (RA), type 2 diabetes, atherosclerosis, and acute myocardial infarction. Blocking IL-1 entered the clinical arena with anakinra, the recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra); IL-1Ra prevents the binding of IL-1α as well as IL-1β to IL-1R1. Quenching IL-1-mediated inflammation prevents the detrimental consequences of tissue damage and organ dysfunction. Although anakinra is presently approved for the treatment of RA and cryopyrin-associated periodic syndromes, off-label use of anakinra far exceeds its approved indications. Dosing of 100 mg of anakinra subcutaneously provides clinically evident benefits within days and for some diseases, anakinra has been used daily for over 12 years. Compared to other biologics, anakinra has an unparalleled record of safety: opportunistic infections, particularly
, are rare even in populations at risk for reactivation of latent infections. Because of this excellent safety profile and relative short duration of action, anakinra can also be used as a diagnostic tool for undefined diseases mediated by IL-1. Although anakinra is presently in clinical trials to treat cancer, this review focuses on anakinra treatment of acute as well as chronic inflammatory diseases.
Early increase of soluble urokinase plasminogen activator receptor (suPAR) serum levels is indicative of increased risk of progression of coronavirus disease 2019 (COVID-19) to respiratory failure. ...The SAVE-MORE double-blind, randomized controlled trial evaluated the efficacy and safety of anakinra, an IL-1α/β inhibitor, in 594 patients with COVID-19 at risk of progressing to respiratory failure as identified by plasma suPAR ≥6 ng ml
, 85.9% (n = 510) of whom were receiving dexamethasone. At day 28, the adjusted proportional odds of having a worse clinical status (assessed by the 11-point World Health Organization Clinical Progression Scale (WHO-CPS)) with anakinra, as compared to placebo, was 0.36 (95% confidence interval 0.26-0.50). The median WHO-CPS decrease on day 28 from baseline in the placebo and anakinra groups was 3 and 4 points, respectively (odds ratio (OR) = 0.40, P < 0.0001); the respective median decrease of Sequential Organ Failure Assessment (SOFA) score on day 7 from baseline was 0 and 1 points (OR = 0.63, P = 0.004). Twenty-eight-day mortality decreased (hazard ratio = 0.45, P = 0.045), and hospital stay was shorter.
Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which ...chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.
Coronavirus disease 2019 (COVID-19) is a condition caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Severe cases of COVID-19 result in acute respiratory distress syndrome ...and death. A detrimental, hyper-inflammatory immune response with excess release of cytokines is the main driver of disease development and of tissue damage in these patients. Thus, repurposing of biologic agents and other pharmacological inhibitors of cytokines used for the treatment of various inflammatory conditions emerged as a logical therapeutic strategy to quench inflammation and improve the clinical outcome of COVID-19 patients. Evaluated agents include the interleukin one receptor blocker anakinra, monoclonal antibodies inhibiting IL-6 tocilizumab and sarilumab, monoclonal antibodies inhibiting granulocyte-monocyte colony stimulating factor and tumor necrosis factor, and Janus kinase inhibitors. In this review, we discuss the efficacy and safety of these therapeutic options based on direct personal experience and on published evidence from observational studies and randomized clinical trials.
Treatment of viral fulminant myocarditis relies on life support measures. Based on studies pointing to a role for the proinflammatory cytokine interleukin-1 in myocardial inflammation and contractile ...dysfunction, we treated a patient with fulminant viral myocarditis with the interleukin-1 receptor blocking agent anakinra. We report the response and discuss the biologic rationale of this novel treatment approach.
Case report.
ICU.
A 36-year-old woman who was hospitalized for fulminant myocarditis with biventricular failure and cardiogenic shock, acutely manifested with hypotension and dyspnea.
Following the progressive, life-threatening collapse of the cardiac function in spite of treatment with venous-arterial extracorporeal membrane oxygenation and mechanical circulatory support with a left ventricular assist device, treatment with the interleukin-1 receptor blocking agent anakinra 100 mg/d was started.
The severe depression of cardiac function responded promptly to interleukin-1 inhibition. Within 4 days of treatment initiation, progressive clinical improvement allowed weaning from extracorporeal membrane oxygenation and removal of the percutaneous left ventricular assist device. The patient was discharged home and remains in excellent health at 12 months.
Clinical and experimental evidence suggests that interleukin-1 blockade is effective against myocardial inflammation and contractile dysfunction, thus representing a promising candidate for the treatment of inflammatory heart failure. Although further confirmation is needed, these encouraging results indicate that anakinra may be a suitable treatment for fulminant myocarditis.
ABSTRACT
Activating mutations in the BRAF-MAPK pathway have been reported in histiocytoses, hematological inflammatory neoplasms characterized by multi-organ dissemination of pro-inflammatory myeloid ...cells. Here, we generate a humanized mouse model of transplantation of human hematopoietic stem and progenitor cells (HSPCs) expressing the activated form of BRAF (
BRAF
V600E
). All mice transplanted with
BRAF
V600E
-expressing HSPCs succumb to bone marrow failure, displaying myeloid-restricted hematopoiesis and multi-organ dissemination of aberrant mononuclear phagocytes. At the basis of this aggressive phenotype, we uncover the engagement of a senescence program, characterized by DNA damage response activation and a senescence-associated secretory phenotype, which affects also non-mutated bystander cells. Mechanistically, we identify TNFα as a key determinant of paracrine senescence and myeloid-restricted hematopoiesis and show that its inhibition dampens inflammation, delays disease onset and rescues hematopoietic defects in bystander cells. Our work establishes that senescence in the human hematopoietic system links oncogene-activation to the systemic inflammation observed in histiocytic neoplasms.
As for all newly-emergent pathogens, SARS-CoV-2 presents with a relative paucity of clinical information and experimental models, a situation hampering both the development of new effective ...treatments and the prediction of future outbreaks. Here, we find that a simple virus-free model, based on publicly available transcriptional data from human cell lines, is surprisingly able to recapitulate several features of the clinically relevant infections. By segregating cell lines (n = 1305) from the CCLE project on the base of their sole angiotensin-converting enzyme 2 (ACE2) mRNA content, we found that overexpressing cells present with molecular features resembling those of at-risk patients, including senescence, impairment of antibody production, epigenetic regulation, DNA repair and apoptosis, neutralization of the interferon response, proneness to an overemphasized innate immune activity, hyperinflammation by IL-1, diabetes, hypercoagulation and hypogonadism. Likewise, several pathways were found to display a differential expression between sexes, with males being in the least advantageous position, thus suggesting that the model could reproduce even the sex-related disparities observed in the clinical outcome of patients with COVID-19. Overall, besides validating a new disease model, our data suggest that, in patients with severe COVID-19, a baseline ground could be already present and, as a consequence, the viral infection might simply exacerbate a variety of latent (or inherent) pre-existing conditions, representing therefore a tipping point at which they become clinically significant.
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