Interleukin-1 regulates follicular T cells during the germinal center reaction.

Introduction: Antibody production and the generation of memory B cells are regulated by T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in germinal centers. However, the precise role of Tfr cells in controlling antibody production is still unclear. We have previously shown that both Tfh and Tfr cells express the IL-1R1 agonist receptor, whereas only Tfr cells express the IL-1R2 decoy and IL-1Ra antagonist receptors. We aimed to investigate the role of IL-1 receptors in the regulation of B cell responses by Tfh and Tfr. Methods: We generated mice with IL-1 receptors inactivated in Tfh or Tfr and measured antibody production and cell activation after immunisation. Results: While IL-1ß levels are increased in the draining lymph node after immunisation, antigen-specific antibody levels and cell phenotypes indicated that IL-1ß can activate both Tfh and Tfr cells through IL-1R1 stimulation. Surprisingly, expression of IL-1R2 and IL-1Ra on Tfr cells does not block IL-1 activation of Tfh cells, but rather prevents IL-1/IL-1R1-mediated early activation of Tfr cells. IL-1Rs also regulate the antibody response to autoantigens and its associated pathophysiology in an experimental lupus model. Discussion: Collectively, our results show that IL-1 inhibitory receptors expressed by Tfr cells prevent their own activation and suppressive function, thus licensing IL-1-mediated activation of Tfh cells after immunisation. Further mechanistic studies should unravel these complex interactions between IL-1ß and follicular helper and regulatory T cells and provide new avenues for therapeutic intervention.

Cyclic nucleotide-induced helical structure activates a TIR immune effector.

Cyclic nucleotide signalling is a key component of antiviral defence in all domains of life. Viral detection activates a nucleotide cyclase to generate a second messenger, resulting in activation of effector proteins. This is exemplified by the metazoan cGAS-STING innate immunity pathway1, which originated in bacteria2. These defence systems require a sensor domain to bind the cyclic nucleotide and are often coupled with an effector domain that, when activated, causes cell death by destroying essential biomolecules3. One example is the Toll/interleukin-1 receptor (TIR) domain, which degrades the essential cofactor NAD+ when activated in response to infection in plants and bacteria2,4,5 or during programmed nerve cell death6. Here we show that a bacterial antiviral defence system generates a cyclic tri-adenylate that binds to a TIR-SAVED effector, acting as the 'glue' to allow assembly of an extended superhelical solenoid structure. Adjacent TIR subunits interact to organize and complete a composite active site, allowing NAD+ degradation. Activation requires extended filament formation, both in vitro and in vivo. Our study highlights an example of large-scale molecular assembly controlled by cyclic nucleotides and reveals key details of the mechanism of TIR enzyme activation.

Cryo-EM structure of an active bacterial TIR-STING filament complex.

Stimulator of interferon genes (STING) is an antiviral signalling protein that is broadly conserved in both innate immunity in animals and phage defence in prokaryotes1-4. Activation of STING requires its assembly into an oligomeric filament structure through binding of a cyclic dinucleotide4-13, but the molecular basis of STING filament assembly and extension remains unknown. Here we use cryogenic electron microscopy to determine the structure of the active Toll/interleukin-1 receptor (TIR)-STING filament complex from a Sphingobacterium faecium cyclic-oligonucleotide-based antiphage signalling system (CBASS) defence operon. Bacterial TIR-STING filament formation is driven by STING interfaces that become exposed on high-affinity recognition of the cognate cyclic dinucleotide signal c-di-GMP. Repeating dimeric STING units stack laterally head-to-head through surface interfaces, which are also essential for human STING tetramer formation and downstream immune signalling in mammals5. The active bacterial TIR-STING structure reveals further cross-filament contacts that brace the assembly and coordinate packing of the associated TIR NADase effector domains at the base of the filament to drive NAD+ hydrolysis. STING interface and cross-filament contacts are essential for cell growth arrest in vivo and reveal a stepwise mechanism of activation whereby STING filament assembly is required for subsequent effector activation. Our results define the structural basis of STING filament formation in prokaryotic antiviral signalling.

Interleukin-37 promotes colitis-associated carcinogenesis via SIGIRR-mediated cytotoxic T cells dysfunction.

Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.

Neutralizing anti-IL-1 receptor antagonist autoantibodies induce inflammatory and fibrotic mediators in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition involving loss of B-cell tolerance and production of autoantibodies. However, the relevant targets and role of these aberrant humoral immune responses are not defined. OBJECTIVE: Our aim was to identify novel autoantibodies and autoantigen targets that promote pathogenic responses in IgG4-RD. METHODS: We sequenced plasmablast antibody repertoires in patients with IgG4-RD. Representative mAbs were expressed and their specificities characterized by using cytokine microarrays. The role of anti-IL-1 receptor antagonist (IL-1RA) autoantibodies was investigated by using in vitro assays. RESULTS: We identified strong reactivity against human IL-1RA by using a clonally expanded plasmablast-derived mAb from a patient with IgG4-RD. Plasma from patients with IgG4-RD exhibited elevated levels of reactivity against IL-1RA compared with plasma from the controls and neutralized IL-1RA activity, resulting in inflammatory and fibrotic mediator production in vitro. IL-1RA was detected in lesional tissues from patients with IgG4-RD. Patients with anti-IL-1RA autoantibodies of the IgG4 subclass had greater numbers of organs affected than did those without anti-IL-1RA autoantibodies. Peptide analyses identified IL-1RA epitopes targeted by anti-IL-1RA antibodies at sites near the IL-1RA/IL-1R interface. Serum from patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) also had elevated levels of anti-IL-1RA autoantibodies compared with those of the controls. CONCLUSION: A subset of patients with IgG4-RD have anti-IL-1RA autoantibodies, which promote proinflammatory and profibrotic meditator production via IL-1RA neutralization. These findings support a novel immunologic mechanism underlying the pathogenesis of IgG4-RD. Anti-IL-1RA autoantibodies are also present in a subset of patients with SLE and RA, suggesting a potential common pathway in multiple autoimmune diseases.

Low-Salt Diet Attenuates B-Cell- and Myeloid-Cell-Driven Experimental Arthritides by Affecting Innate as Well as Adaptive Immune Mechanisms.

A link between high sodium chloride (salt) intake and the development of autoimmune diseases was previously reported. These earlier studies demonstrated exacerbation of experimental autoimmune encephalomyelitis and colitis by excess salt intake associated with Th17- and macrophage-mediated mechanisms. Little is known about the impact of dietary salt intake on experimental arthritides. Here, we investigated if salt restriction can exert beneficial effects on collagen-induced arthritis (CIA) and K/BxN serum transfer-induced arthritis (STIA). CIA depends on both adaptive and innate immunity, while STIA predominantly mimics the innate immune cell-driven effector phase of arthritis. In both models, low salt (LS) diet significantly decreased arthritis severity compared to regular salt (RS) and high salt (HS) diet. We did not observe an aggravation of arthritis with HS diet compared to RS diet. Remarkably, in STIA, LS diet was as effective as IL-1 receptor blocking treatment. Complement-fixing anti-CII IgG2a antibodies are associated with inflammatory cell infiltration and cartilage destruction. LS diet reduced anti-CII IgG2a levels in CIA and decreased the anti-CII IgG2a/IgG1 ratios pointing toward a more Th2-like response. Significantly less inflammatory joint infiltrates and cartilage breakdown associated with reduced protein concentrations of IL-1 beta (CIA and STIA), IL-17 (CIA), and the monocyte chemoattractant protein-1 (MCP-1) (CIA) were detected in mice receiving LS diet compared to HS diet. However, we did not find a reduced IL-17A expression in CD4+ T cells upon salt restriction in CIA. Analysis of mRNA transcripts and immunoblots revealed a link between LS diet and inhibition of the p38 MAPK (mitogen-activated protein kinase)/NFAT5 (nuclear factor of activated T-cells 5) signaling axis in STIA. Further experiments indicated a decreased leukodiapedesis under LS conditions. In conclusion, dietary salt restriction ameliorates CIA and STIA, indicating a beneficial role of LS diet during both the immunization and effector phase of immune-mediated arthritides by predominantly modulating the humoral immunity and the activation status of myeloid lineage cells. Hence, salt restriction might represent a supportive dietary intervention not only to reduce cardiovascular risk, but also to improve human inflammatory joint diseases like rheumatoid arthritis.

TIRAP in the Mechanism of Inflammation.

The Toll-interleukin-1 Receptor (TIR) domain-containing adaptor protein (TIRAP) represents a key intracellular signalling molecule regulating diverse immune responses. Its capacity to function as an adaptor molecule has been widely investigated in relation to Toll-like Receptor (TLR)-mediated innate immune signalling. Since the discovery of TIRAP in 2001, initial studies were mainly focused on its role as an adaptor protein that couples Myeloid differentiation factor 88 (MyD88) with TLRs, to activate MyD88-dependent TLRs signalling. Subsequent studies delineated TIRAP's role as a transducer of signalling events through its interaction with non-TLR signalling mediators. Indeed, the ability of TIRAP to interact with an array of intracellular signalling mediators suggests its central role in various immune responses. Therefore, continued studies that elucidate the molecular basis of various TIRAP-protein interactions and how they affect the signalling magnitude, should provide key information on the inflammatory disease mechanisms. This review summarizes the TIRAP recruitment to activated receptors and discusses the mechanism of interactions in relation to the signalling that precede acute and chronic inflammatory diseases. Furthermore, we highlighted the significance of TIRAP-TIR domain containing binding sites for several intracellular inflammatory signalling molecules. Collectively, we discuss the importance of the TIR domain in TIRAP as a key interface involved in protein interactions which could hence serve as a therapeutic target to dampen the extent of acute and chronic inflammatory conditions.

The role of interleukin-1ß in the immune response to contact allergens.

Interleukin-1ß (IL-1ß) is an important pro-inflammatory cytokine that has an effect on almost every cell lineage in the body. By blocking IL-1ß and investigating the IL-1ß signaling pathway, several studies have demonstrated a central role of IL-1ß in the response to contact allergens. This review summarizes the current literature regarding the basic immunological mechanisms mediated by IL-1ß in the different phases of allergic contact dermatitis (ACD) and highlights potential IL-1ß-targeted treatment options, which in the future may be relevant in the treatment of patients with ACD. This review is based primarily on studies using various mouse models and human in vitro studies, since clinical studies on the effect of IL-1ß in ACD are lacking.

IL-1R1-Dependent Signals Improve Control of Cytosolic Virulent Mycobacteria In Vivo.

Mycobacterium tuberculosis infections claim more than a million lives each year, and better treatments or vaccines are required. A crucial pathogenicity factor is translocation from phagolysosomes to the cytosol upon phagocytosis by macrophages. Translocation from the phagolysosome to the cytosol is an ESX-1-dependent process, as previously shown in vitro Here, we show that in vivo, mycobacteria also translocate to the cytosol but mainly when host immunity is compromised. We observed only low numbers of cytosolic bacilli in mice, armadillos, zebrafish, and patient material infected with M. tuberculosis, M. marinum, or M. leprae In contrast, when innate or adaptive immunity was compromised, as in severe combined immunodeficiency (SCID) or interleukin-1 receptor 1 (IL-1R1)-deficient mice, significant numbers of cytosolic M. tuberculosis bacilli were detected in the lungs of infected mice. Taken together, in vivo, translocation to the cytosol of M. tuberculosis is controlled by adaptive immune responses as well as IL-1R1-mediated signals.IMPORTANCE For decades, Mycobacterium tuberculosis has been one of the deadliest pathogens known. Despite infecting approximately one-third of the human population, no effective treatment or vaccine is available. A crucial pathogenicity factor is subcellular localization, as M. tuberculosis can translocate from phagolysosome to the cytosol in macrophages. The situation in vivo is more complicated. In this study, we establish that high-level cytosolic escape of mycobacteria can indeed occur in vivo but mainly when host resistance is compromised. The IL-1 pathway is crucial for the control of the number of cytosolic mycobacteria. The establishment that immune signals result in the clearance of cells containing cytosolic mycobacteria connects two important fields, cell biology and immunology, which is vital for the understanding of the pathology of M. tuberculosis.

Keratinocyte IL-36 Receptor/MyD88 Signaling Mediates Malassezia-Induced IL-17-Dependent Skin Inflammation.

BACKGROUND: Among skin commensal fungi, lipophilic Malassezia species exist on nearly all human skin surfaces. The pathophysiology of Malassezia-associated skin diseases remains poorly understood due in part to the lack of appropriate animal models. Our objective was to investigate the mechanisms underlying Malassezia-induced skin inflammation using a novel murine model that physiologically recapitulates Malassezia skin infection. METHODS: Mice were inoculated epicutaneously with Malassezia yeasts without barrier disruption and in the absence of external lipid supplementation. Skin inflammation, lesional fungal loads, and expression of cytokines and antimicrobial peptides were evaluated in wild-type and mutant mouse strains. RESULTS: Malassezia-induced skin inflammation and epidermal thickening were observed on day 4 after inoculation in wild-type mice. High fungal burdens were detected in the cornified layer on day 2 and decreased thereafter with near complete clearance by day 7 after inoculation. Malassezia-induced skin inflammation and fungal clearance by the host were interleukin-17 (IL-17) dependent with contribution of group 3 innate lymphoid cells. Moreover, IL-17-dependent skin inflammation was mediated through IL-36 receptor and keratinocyte MyD88 signaling. CONCLUSION: Using a new skin infection model, it is shown that Malassezia-induced IL-17- dependent skin inflammation and control of fungal infection are mediated via keratinocyte IL-36 receptor/MyD88 signaling.

Homeostatic regulation of T follicular helper and antibody response to particle antigens by IL-1Ra of medullary sinus macrophage origin.

Hepatitis B virus (HBV) vaccines are composed of surface antigen HBsAg that spontaneously assembles into subviral particles. Factors that impede its humoral immunity in 5% to 10% of vaccinees remain elusive. Here, we showed that the low-level interleukin-1 receptor antagonist (IL-1Ra) can predict antibody protection both in mice and humans. Mechanistically, murine IL-1Ra-inhibited T follicular helper (Tfh) cell expansion and subsequent germinal center (GC)-dependent humoral immunity, resulting in significantly weakened protection against the HBV challenge. Compared to soluble antigens, HBsAg particle antigen displayed a unique capture/uptake and innate immune activation, including IL-1Ra expression, preferably of medullary sinus macrophages. In humans, a unique polymorphism in the RelA/p65 binding site of IL-1Ra enhancer associated IL-1Ra levels with ethnicity-dependent vaccination outcome. Therefore, the differential IL-1Ra response to particle antigens probably creates a suppressive milieu for Tfh/GC development, and neutralization of IL-1Ra would resurrect antibody response in HBV vaccine nonresponders.

Differential signaling patterns of stimulated bone marrow-derived dendritic cells under α1-antitrypsin-enriched conditions.

Dendritic cells (DCs) mature upon an inflammatory trigger. However, an inflammatory trigger can lead to a semi-mature phenotype, allowing DCs to evoke tolerance and expedite the resolution of inflammation. This duality likely involves context-dependent modulation of inflammatory signaling. Human α1-antitrypsin (hAAT) promotes semimature DCs. We examined changes in a wide spectrum of signaling cascades in stimulated murine bone marrow-derived cells with hAAT. Upon stimulation by IL-1ß+IFNγ, hAAT-treated cells depicted an attenuated calcium flux. Disrupting PKA or NF-κB pathways revoked only some hAAT-mediated outcomes. hAAT-treated cells exhibited a distict pattern of kinase phosphorylation. hAAT-mediated increase in Treg cells in-vitro required intact inflammatory signaling pathways. Taken together, hAAT appears to require a stimulated microenvironment to promote inflammatory resolution, setting it aside from classical anti-inflammatory agents. Further studies are required to identify the specific molecules targeted by hAAT that mediate these and other outcomes.

Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function.

The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non-small cell lung cancer (NSCLC), accumulation of anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of protumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased natural killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL37. MARCO-expressing TAMs blocked cytotoxic T-cell and NK-cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO+ macrophages enhanced regulatory T (Treg) cell proliferation and IL10 production and diminished CD8 T-cell activities. Targeting MARCO or IL37 receptor (IL37R) by antibody or CRISPR knockout of IL37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and antitumoral capacity of NK cells and T cells and downmodulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK- and T-cell antitumor activities. SIGNIFICANCE: This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvironment in patients with lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/4/956/F1.large.jpg.

IL-37d Negatively Regulates NLRP3 Transcription via Receptor-mediated Pathway and Alleviates DSS-induced Colitis.

BACKGROUND: Interleukin-37 (IL-37) is a new negative immune regulator. It has 5 splicing forms, IL-37a-e, and most research mainly focuses on IL-37b functions in diverse diseases. Our previous research found that IL-37d inhibits lipopolysaccharide-induced inflammation in endotoxemia through a mechanism different from that of IL-37b. However, whether IL-37d plays a role in colitis and the underlying mechanisms is still obscure. Herein, we identified whether IL-37d regulates NLRP3 inflammasome activity and determined its effect on colitis. METHODS: NLRP3 inflammasome in macrophages from IL-37d transgenic (IL-37dtg) and control wild type (WT) mice were activated by lipopolysaccharide and adenosine 5'-triphosphate. The expression of NLRP3 inflammasome components and its downstream effector, IL-1ß, were detected by real-time polymerase chain reaction, western blot, and ELISA. The models of alum-induced peritonitis and dextran sodium sulfate (DSS)-induced colitis were used to investigate the function of IL-37d on regulating the activity of NLRP3 inflammasome in vivo. RESULTS: Our results showed that the activation of NLRP3 inflammasome in macrophage and alum-induced peritonitis was inhibited by IL-37d. Strikingly, IL-37d suppressed NLRP3 expression at the priming step via inhibiting NF-κB activation by transcriptional profiling. Moreover, the recombinant protein IL-37d attenuated NLRP3 inflammasome activation and the production of IL-1ß, which could be reversed by IL-1R8 knockdown. Finally, IL-37d transgenic mice resisted DSS-induced acute colitis and NLRP3 inflammasome activation. CONCLUSION: Interleukin-37d inhibits overactivation of the NLRP3 inflammasome through regulating NLRP3 transcription in an IL-1R8 receptor-mediated signaling pathway.

Reduced concentrations of the B cell cytokine interleukin 38 are associated with cardiovascular disease risk in overweight subjects.

The IL-1 family member IL-38 (IL1F10) suppresses inflammatory and autoimmune conditions. Here, we report that plasma concentrations of IL-38 in 288 healthy Europeans correlate positively with circulating memory B cells and plasmablasts. IL-38 correlated negatively with age (p = 0.02) and was stable in 48 subjects for 1 year. In comparison with primary keratinocytes, IL1F10 expression in CD19+ B cells from PBMC was lower, whereas cell-associated IL-38 expression was comparable. In vitro, IL-38 is released from CD19+ B cells after stimulation with rituximab. Intravenous LPS in humans failed to induce circulating IL-38, compared to 100-fold induction of IL-6 and IL-1 receptor antagonist. In a cohort of 296 subjects with body mass index > 27 at high risk for cardiovascular disease, IL-38 plasma concentrations were significantly lower than in healthy subjects (p < 0.0001), and lowest in those with metabolic syndrome (p < 0.05). IL-38 also correlated inversely with high sensitivity C-reactive protein (p < 0.01), IL-6, IL-1Ra, and leptin (p < 0.05). We conclude that a relative deficiency of the B cell product IL-38 is associated with increased systemic inflammation in aging, cardiovascular and metabolic disease, and is consistent with IL-38 as an anti-inflammatory cytokine.

Ulcerative Colitis-associated E. coli pathobionts potentiate colitis in susceptible hosts.

Ulcerative colitis (UC) is a chronic inflammatory condition linked to intestinal microbial dysbiosis, including the expansion of E. coli strains related to extra-intestinal pathogenic E. coli. These "pathobionts" exhibit pathogenic properties, but their potential to promote UC is unclear due to the lack of relevant animal models. Here, we established a mouse model using a representative UC pathobiont strain (p19A), and mice lacking single immunoglobulin and toll-interleukin 1 receptor domain (SIGIRR), a deficiency increasing susceptibility to gut infections. Strain p19A was found to adhere to the cecal mucosa of Sigirr -/- mice, causing modest inflammation. Moreover, it dramatically worsened dextran sodium sulfate-induced colitis. This potentiation was attenuated using a p19A strain lacking α-hemolysin genes, or when we targeted pathobiont adherence using a p19A strain lacking the adhesin FimH, or following treatment with FimH antagonists. Thus, UC pathobionts adhere to the intestinal mucosa, and worsen the course of colitis in susceptible hosts.

Talin1 controls dendritic cell activation by regulating TLR complex assembly and signaling.

Talin critically controls integrin-dependent cell migration, but its regulatory role in skin dendritic cells (DCs) during inflammatory responses has not been investigated. Here, we show that talin1 regulates not only integrin-dependent Langerhans cell (LC) migration, but also MyD88-dependent Toll-like receptor (TLR)-stimulated DC activation. Talin1-deficient LCs failed to exit the epidermis, resulting in reduced LC migration to skin-draining lymph nodes (sdLNs) and defective skin tolerance induction, while talin1-deficient dermal DCs unexpectedly accumulated in the dermis despite their actomyosin-dependent migratory capabilities. Furthermore, talin1-deficient DCs exhibited compromised chemotaxis, NFκB activation, and proinflammatory cytokine production. Mechanistically, talin1 was required for the formation of preassembled TLR complexes in DCs at steady state via direct interaction with MyD88 and PIP5K. Local production of PIP2 by PIP5K then recruited TIRAP to the preassembled complexes, which were required for TLR signalosome assembly during DC activation. Thus, talin1 regulates MyD88-dependent TLR signaling pathways in DCs through a novel mechanism with implications for antimicrobial and inflammatory immune responses.

IL-1R Regulates Disease Tolerance and Cachexia in Toxoplasma gondii Infection.

Toxoplasma gondii is an obligate intracellular parasite that establishes life-long infection in a wide range of hosts, including humans and rodents. To establish a chronic infection, pathogens often exploit the trade-off between resistance mechanisms, which promote inflammation and kill microbes, and tolerance mechanisms, which mitigate inflammatory stress. Signaling through the type I IL-1R has recently been shown to control disease tolerance pathways in endotoxemia and Salmonella infection. However, the role of the IL-1 axis in T. gondii infection is unclear. In this study we show that IL-1R-/- mice can control T. gondii burden throughout infection. Compared with wild-type mice, IL-1R-/- mice have more severe liver and adipose tissue pathology during acute infection, consistent with a role in acute disease tolerance. Surprisingly, IL-1R-/- mice had better long-term survival than wild-type mice during chronic infection. This was due to the ability of IL-1R-/- mice to recover from cachexia, an immune-metabolic disease of muscle wasting that impairs fitness of wild-type mice. Together, our data indicate a role for IL-1R as a regulator of host homeostasis and point to cachexia as a cost of long-term reliance on IL-1-mediated tolerance mechanisms.

Interleukin-1 receptor antagonist, interleukin-2 receptor alpha subunit and amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: To clarify the causal associations of interleukin-1 receptor antagonist (IL-1ra) and interleukin-2 receptor alpha subunit (IL-2rα) with the risk of amyotrophic lateral sclerosis (ALS). METHODS: A two-sample Mendelian randomization study design was employed. Single-nucleotide polymorphisms associated with IL-1ra (n = 2) and IL-2rα (n = 1) at the genome-wide significance level were used as unbiased instrumental variables. Summary-level data for ALS were obtained from Project MinE, an international collaboration consortium with 12 577 ALS cases and 23 475 controls of European descent. RESULTS: Genetic predisposition to higher levels of IL-1ra was significantly associated with lower odds of ALS. For a 1-SD increase of circulating IL-1ra levels, the odds ratio of ALS was 0.64 (95% confidence intervals, 0.46-0.88; P = 0.005). There was a borderline inverse association between IL-2rα levels and ALS (odds ratio, 0.91; 95% confidence intervals, 0.83-1.00; P = 0.058). CONCLUSIONS: Interleukin-1 receptor antagonist levels were inversely associated with ALS, suggesting that interleukin-1 inhibitors may lower the risk of this always fatal disease. The role of IL-2rα levels in ALS needs further verification in causal inference studies with larger sample sizes.