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Key Points Interleukin-22 (IL-22) is a cytokine that is produced during inflammation by activated T cells, including T helper 22 (T H 22), T H 17 and T H 1 cells, and by subsets of innate lymphoid cells (ILCs). Via its transmembrane receptor complex composed of IL-22 receptor 1 (IL-22R1) and IL-10R2, IL-22 mainly influences epithelial cells, hepatocytes, pancreatic acinar cells and related stem cells. In many of its target cells, IL-22 enhances the production of antibacterial proteins, inhibits their differentiation and/or increases their proliferation, and protects them against damage. Furthermore, it potentiates the tumour necrosis factor (TNF)- and IL-17-induced production of pro-inflammatory mediators. Therapeutic strengthening of the IL-22–IL-22R system — for example, through the application of recombinant IL-22 or IL-22-inducing small molecules — might have a beneficial impact in liver and pancreas damage, ulcerative colitis, graft-versus-host disease and transplantation of IL-22R1-expressing organs. Conversely, the regenerative and protective effects mediated via IL-22R1 might have a pathogenetic role in, for example, psoriasis and tumorigenesis of IL-22R1-expressing cancers, which suggests that attenuation of the IL22–IL-22R system might be beneficial in such situations. Targeting IL-22R1 (for example, with antibodies) may produce better clinical results than IL-22 neutralization, because two other cytokines — IL-20 and IL-24 — are often co-produced during inflammation and can mediate IL-22-like effects in an IL-22R1-dependent manner. Owing to the lack of IL-22R1 expression on haematopoietic cells, therapeutic modulation of the IL-22–IL-22R1 system is not expected to be accompanied by severe immunological side effects. Interleukin 22 receptor 1 (IL-22R1) activity affects the development and course of disorders including psoriasis, ulcerative colitis, certain infections and tumours, without directly regulating immune cell function. Here, the authors describe the biology of IL-22 and highlight the therapeutic potential of modulating the activity of IL-22 and/or its receptor IL-22R1. Interleukin-22 (IL-22) is a key effector molecule that is produced by activated T cells, including T helper 22 (T H 22) cells, T H 17 cells and T H 1 cells, as well as subsets of innate lymphoid cells. Although IL-22 can act synergistically with IL-17 or tumour necrosis factor, some important functions of IL-22 are unique to this cytokine. Data obtained over the past few years indicate that the IL-22–IL-22 receptor subunit 1 (IL-22R1) system has a high potential clinical relevance in psoriasis, ulcerative colitis, graft-versus-host disease, certain infections and tumours, as well as in liver and pancreas damage. This Review highlights current knowledge of the biology of the IL-22–IL-22R1 system, its role in inflammation, tissue protection, regeneration and antimicrobial defence, as well as the positive and potentially negative consequences of its therapeutic modulation.

T-cell redirecting bispecific antibodies (BsAbs) and chimeric antigen receptor T cells (CAR T cells) have revolutionised multiple myeloma therapy, but adverse events such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), cytopenias, hypogammaglobulinaemia, and infections are common. This Policy Review presents a consensus from the European Myeloma Network on the prevention and management of these adverse events. Recommended measures include premedication, frequent assessing for symptoms and severity of cytokine release syndrome, step-up dosing for several BsAbs and some CAR T-cell therapies; corticosteroids; and tocilizumab in the case of cytokine release syndrome. Other anti-IL-6 drugs, high-dose corticosteroids, and anakinra might be considered in refractory cases. ICANS often arises concomitantly with cytokine release syndrome. Glucocorticosteroids in increasing doses are recommended if needed, as well as anakinra if the response is inadequate, and anticonvulsants if convulsions occur. Preventive measures against infections include antiviral and antibacterial drugs and administration of immunoglobulins. Treatment of infections and other complications is also addressed.

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects. Here, the authors computationally designed and produced small protein antagonists to target IL-6 and IL-1β signaling to develop modulators of CRS.

A study of families from southern Tunisia affected by general pustular psoriasis uncovered the genetic cause of their disease: a mutation affecting the function of the interleukin-36–receptor antagonist. Psoriasis is a chronic inflammatory skin disease affecting 2 to 3% of persons of European descent. 1 Psoriasis vulgaris, the most common form of the disease, accounts for 80% of cases and has a strong, albeit complex, genetic component. 2 Numerous chromosomal loci have been implicated in genomewide association studies, but analyses of these loci have yielded only a few candidate genes, which mediate inflammatory cytokine signaling and adaptive immune responses. 3 – 5 The disease follows mendelian transmission in a small minority of families. Generalized pustular psoriasis is a life-threatening, multisystemic inflammatory disease involving repeated flare-ups of sudden onset, which are characterized by . . .

IL-1 has an important role in the pathogenesis of many hereditary and non-hereditary autoinflammatory diseases. This Review examines the biological functions of IL-1 and the use of IL-1-targeting agents in the treatment of various human diseases. Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1α and IL-1β, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1β processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases. Key Points Interleukin (IL)-1, which includes IL-1α and IL-1β, exerts strong proinflammatory activities and has a major role in host responses to exogenous and endogenous noxious stimuli The proinflammatory activities of IL-1 are controlled by several endogenous inhibitors, such as IL-1 receptor antagonist (IL-1Ra), membrane-bound and soluble IL-1 receptor type II and IL-1 receptor accessory protein Numerous exogenous (for example, microbial components and asbestos) and endogenous (for example, monosodium urate and calcium pyrophosphate dihydrate crystals) agents can activate caspase 1, which induces release of bioactive IL-1β The role of IL-1 in disease is exemplified by the description of hereditary autoinflammatory diseases caused by excessive IL-1 signaling secondary to either IL-1β overproduction or IL-1Ra deficiency A beneficial effect of targeting IL-1 has been described in several hereditary and non-hereditary autoinflammatory diseases The potential role of IL-1 in the pathogenesis of type 2 diabetes and smoldering myeloma has been supported by the results of recent clinical trials

IL-1β is a proinflammatory mediator with roles in innate and adaptive immunity. Here we show that IL-1β contributes to autoimmune arthritis by inducing osteoclastogenic capacity in Tregs. Using mice with joint inflammation arising through deficiency of the IL-1 receptor antagonist (Il1rn-/-), we observed that IL-1β blockade attenuated disease more effectively in early arthritis than in established arthritis, especially with respect to bone erosion. Protection was accompanied by a reduction in synovial CD4+Foxp3+ Tregs that displayed preserved suppressive capacity and aerobic metabolism but aberrant expression of RANKL and a striking capacity to drive RANKL-dependent osteoclast differentiation. Both Il1rn-/- Tregs and wild-type Tregs differentiated with IL-1β accelerated bone erosion upon adoptive transfer. Human Tregs exhibited analogous differentiation, and corresponding RANKLhiFoxp3+ T cells could be identified in rheumatoid arthritis synovial tissue. Together, these findings identify IL-1β-induced osteoclastogenic Tregs as a contributor to bone erosion in arthritis.

We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the ‘interleukin 1 (IL-1)–interleukin 1 receptor antagonist (IL-1ra)’ axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.RNA vaccines have been associated with high reactogenicity. Mellman and colleagues demonstrate that lipid-formulated RNA vaccines trigger IL-1 production and inflammation in humans but this pathway is dampened in mice.

Background Perturbation of commensal intestinal microbiota has been associated with several autoimmune diseases. Mice deficient in interleukin-1 receptor antagonist ( Il1rn −/− mice) spontaneously develop autoimmune arthritis and are susceptible to other autoimmune diseases such as psoriasis, diabetes, and encephalomyelitis; however, the mechanisms of increased susceptibility to these autoimmune phenotypes are poorly understood. We investigated the role of interleukin-1 receptor antagonist (IL-1Ra) in regulation of commensal intestinal microbiota, and assessed the involvement of microbiota subsets and innate and adaptive mucosal immune responses that underlie the development of spontaneous arthritis in Il1rn − / − mice. Results Using high-throughput 16S rRNA gene sequencing, we show that IL-1Ra critically maintains the diversity and regulates the composition of intestinal microbiota in mice. IL-1Ra deficiency reduced the intestinal microbial diversity and richness, and caused specific taxonomic alterations characterized by overrepresented Helicobacter and underrepresented Ruminococcus and Prevotella . Notably, the aberrant intestinal microbiota in IL1rn − / − mice specifically potentiated IL-17 production by intestinal lamina propria (LP) lymphocytes and skewed the LP T cell balance in favor of T helper 17 (Th17) cells, an effect transferable to WT mice by fecal microbiota. Importantly, LP Th17 cell expansion and the development of spontaneous autoimmune arthritis in IL1rn − / − mice were attenuated under germ-free condition. Selective antibiotic treatment revealed that tobramycin-induced alterations of commensal intestinal microbiota, i.e. , reduced Helicobacter , Flexispira , Clostridium , and Dehalobacterium , suppressed arthritis in IL1rn − / − mice. The arthritis phenotype in IL1rn − / − mice was previously shown to depend on Toll-like receptor 4 (TLR4). Using the ablation of both IL-1Ra and TLR4, we here show that the aberrations in the IL1rn − / − microbiota are partly TLR4-dependent. We further identify a role for TLR4 activation in the intestinal lamina propria production of IL-17 and cytokines involved in Th17 differentiation preceding the onset of arthritis. Conclusions These findings identify a critical role for IL1Ra in maintaining the natural diversity and composition of intestinal microbiota, and suggest a role for TLR4 in mucosal Th17 cell induction associated with the development of autoimmune disease in mice.

Fatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue. Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4. There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group. This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS. ClinicalTrials.gov NCT00683345.