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Progression of tuberculosis is tightly linked to a disordered immune balance, resulting in inability of the host to restrict intracellular bacterial replication and its subsequent dissemination. The immune response is mainly characterized by an orchestrated recruitment of inflammatory cells secreting cytokines. This response results from the activation of innate immunity receptors that trigger downstream intracellular signaling pathways involving adaptor proteins such as the TIR-containing adaptor protein (Tirap). In humans, resistance to tuberculosis is associated with a loss-of-function in Tirap. Here, we explore how genetic deficiency in Tirap impacts resistance to Mycobacterium tuberculosis (Mtb) infection in a mouse model and ex vivo . Interestingly, compared to wild type littermates, Tirap heterozygous mice were more resistant to Mtb infection. Upon investigation at the cellular level, we observed that mycobacteria were not able to replicate in Tirap-deficient macrophages compared to wild type counterparts. We next showed that Mtb infection induced Tirap expression which prevented phagosomal acidification and rupture. We further demonstrate that the Tirap-mediated anti-tuberculosis effect occurs through a Cish-dependent signaling pathway. Our findings provide new molecular evidence about how Mtb manipulates innate immune signaling to enable intracellular replication and survival of the pathogen, thus paving the way for host-directed approaches to treat tuberculosis.

Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R–MyD88–IRAK2–PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of IRAK2 Myddosome to mitochondria outer membranes via recognition by TOM20, followed by TIMM50-guided translocation of IRAK2 into mitochondria inner membranes, to suppress oxidative phosphorylation and fatty acid oxidation, thereby attenuating energy expenditure. Adipocyte-specific MyD88 or IRAK2 deficiency reduced high-fat-diet-induced weight gain, increased energy expenditure and ameliorated insulin resistance, associated with a smaller adipocyte size and increased cristae formation. IRAK2 kinase inactivation also reduced high-fat diet-induced metabolic diseases. Mechanistically, IRAK2 suppressed respiratory super-complex formation via interaction with PHB1 and OPA1 upon stimulation of IL-1. Taken together, our results suggest that the IRAK2 Myddosome functions as a critical link between inflammation and metabolism, representing a novel therapeutic target for patients with obesity. Obesity is often accompanied by chronic inflammation. Li and colleagues show that, in mice fed high-fat diets, IL-1 signaling in adipocytes induces an unconventional IRAK2 translocation to mitochondria and suppresses respiratory super-complex formation to alter mitochondrial function, and exacerbates obesity.

MYD88 signalling in cancer RNA interference screening and high-throughput RNA resequencing have been used to reveal oncogenic mutations in the signalling adapter MYD88 in human lymphomas. One amino acid substitution, L265P, was found in 29% of biopsies from patients with the activated B-cell-like subtype of diffuse large B-cell lymphoma. The same mutation was observed with lower frequency in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, were shown to activate the pathway and promote cancer cell survival. This study finds frequent mutations in MYD88 in the activated B-cell-like subtype of diffuse large B-cell lymphoma and, with lower frequency, in mucosa-associated lymphoid tissue lymphomas. MYD88 mediates signalling by Toll-like receptors, and the mutations, most of which affect the same amino acid, are shown to activate the pathway and promote cancer cell survival. The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) remains the least curable form of this malignancy despite recent advances in therapy 1 . Constitutive nuclear factor (NF)-κB and JAK kinase signalling promotes malignant cell survival in these lymphomas, but the genetic basis for this signalling is incompletely understood. Here we describe the dependence of ABC DLBCLs on MYD88, an adaptor protein that mediates toll and interleukin (IL)-1 receptor signalling 2 , 3 , and the discovery of highly recurrent oncogenic mutations affecting MYD88 in ABC DLBCL tumours. RNA interference screening revealed that MYD88 and the associated kinases IRAK1 and IRAK4 are essential for ABC DLBCL survival. High-throughput RNA resequencing uncovered MYD88 mutations in ABC DLBCL lines. Notably, 29% of ABC DLBCL tumours harboured the same amino acid substitution, L265P, in the MYD88 Toll/IL-1 receptor (TIR) domain at an evolutionarily invariant residue in its hydrophobic core. This mutation was rare or absent in other DLBCL subtypes and Burkitt’s lymphoma, but was observed in 9% of mucosa-associated lymphoid tissue lymphomas. At a lower frequency, additional mutations were observed in the MYD88 TIR domain, occurring in both the ABC and germinal centre B-cell-like (GCB) DLBCL subtypes. Survival of ABC DLBCL cells bearing the L265P mutation was sustained by the mutant but not the wild-type MYD88 isoform, demonstrating that L265P is a gain-of-function driver mutation. The L265P mutant promoted cell survival by spontaneously assembling a protein complex containing IRAK1 and IRAK4, leading to IRAK4 kinase activity, IRAK1 phosphorylation, NF-κB signalling, JAK kinase activation of STAT3, and secretion of IL-6, IL-10 and interferon-β. Hence, the MYD88 signalling pathway is integral to the pathogenesis of ABC DLBCL, supporting the development of inhibitors of IRAK4 kinase and other components of this pathway for the treatment of tumours bearing oncogenic MYD88 mutations.

MyD88, IRAK4 and IRAK2 are critical signalling mediators of the TLR/IL1-R superfamily. Here we report the crystal structure of the MyD88–IRAK4–IRAK2 death domain (DD) complex, which surprisingly reveals a left-handed helical oligomer that consists of 6 MyD88, 4 IRAK4 and 4 IRAK2 DDs. Assembly of this helical signalling tower is hierarchical, in which MyD88 recruits IRAK4 and the MyD88–IRAK4 complex recruits the IRAK4 substrates IRAK2 or the related IRAK1. Formation of these Myddosome complexes brings the kinase domains of IRAKs into proximity for phosphorylation and activation. Composite binding sites are required for recruitment of the individual DDs in the complex, which are confirmed by mutagenesis and previously identified signalling mutations. Specificities in Myddosome formation are dictated by both molecular complementarity and correspondence of surface electrostatics. The MyD88–IRAK4–IRAK2 complex provides a template for Toll signalling in Drosophila and an elegant mechanism for versatile assembly and regulation of DD complexes in signal transduction. Signalling immunity Toll-family receptors and some proteins containing the death domain protein module play key roles in innate immunity. This paper describes the first crystal structure of the ternary death domain complex comprising MyD88, IRAK4 and IRAK2, three critical signalling mediators of Toll-like receptors. The structure reveals how MyD88, IRAK4 and IRAK2 cooperate in TLR/IL1-R signalling. Toll-like receptors (TLRs) are crucial to innate immunity. Activation of these proteins, and of receptors for the pro-inflammatory cytokines IL-1 and IL-18, leads to the recruitment of adaptor proteins such as MyD88. These in turn interact with further proteins such as IRAK2 and IRAK4. The crystal structure of the MyD88–IRAK2–IRAK4 death domain complex is now reported, explaining how these three proteins cooperate in TLR/IL-1R signalling.

Monocytes and monocyte-derived macrophages (MDMs) from blood circulation infiltrate glioblastoma (GBM) and promote growth. Here, we show that PDGFB-driven GBM cells induce the expression of the potent proinflammatory cytokine IL-1β in MDM, which engages IL-1R1 in tumor cells, activates the NF-κB pathway, and subsequently leads to induction of monocyte chemoattractant proteins (MCPs). Thus, a feedforward paracrine circuit of IL-1β/IL-1R1 between tumors and MDM creates an interdependence driving PDGFB-driven GBM progression. Genetic loss or locally antagonizing IL-1β/IL-1R1 leads to reduced MDM infiltration, diminished tumor growth, and reduced exhausted CD8+ T cells and thereby extends the survival of tumor-bearing mice. In contrast to IL-1β, IL-1α exhibits antitumor effects. Genetic deletion of Il1a/b is associated with decreased recruitment of lymphoid cells and loss-of-interferon signaling in various immune populations and subsets of malignant cells and is associated with decreased survival time of PDGFB-driven tumor-bearing mice. In contrast to PDGFB-driven GBM, Nf1-silenced tumors have a constitutively active NF-κB pathway, which drives the expression of MCPs to recruit monocytes into tumors. These results indicate local antagonism of IL-1β could be considered as an effective therapy specifically for proneural GBM.

Chronic stress is associated with increased anxiety, cognitive deficits, and post-traumatic stress disorder. Repeated social defeat (RSD) in mice causes long-term stress-sensitization associated with increased microglia activation, monocyte accumulation, and enhanced interleukin (IL)-1 signaling in endothelia and neurons. With stress-sensitization, mice have amplified neuronal, immune, and behavioral responses to acute stress 24 days later. This is clinically relevant as it shares key aspects with post-traumatic stress disorder. The mechanisms underlying stress-sensitization are unclear, but enhanced fear memory may be critical. The purpose of this study was to determine the influence of microglia and IL-1R1 signaling in neurons in the development of sensitization and increased fear memory after RSD. Here, RSD accelerated fear acquisition, delayed fear extinction, and increased cued-based freezing at 0.5 day. The enhancement in contextual fear memory after RSD persisted 24 days later. Next, microglia were depleted with a CSF1R antagonist prior to RSD and several parameters were assessed. Microglia depletion blocked monocyte recruitment to the brain. Nonetheless, neuronal reactivity (pCREB) and IL-1β RNA expression in the hippocampus and enhanced fear memory after RSD were microglial-independent. Because IL-1β RNA was prominent in the hippocampus after RSD even with microglia depletion, IL-1R1 mediated signaling in glutamatergic neurons was assessed using neuronal Vglut2 + / IL-1R1 −/− mice. RSD-induced neuronal reactivity (pCREB) in the hippocampus and enhancement in fear memory were dependent on neuronal IL-1R1 signaling. Furthermore, single-nuclei RNA sequencing (snRNAseq) showed that RSD influenced transcription in specific hippocampal neurons (DG neurons, CA2/3, CA1 neurons) associated with glutamate signaling, inflammation and synaptic plasticity, which were neuronal IL-1R1-dependent. Furthermore, snRNAseq data provided evidence that RSD increased CREB, BDNF, and calcium signaling in DG neurons in an IL-1R1-dependent manner. Collectively, increased IL-1R1-mediated signaling (monocytes/microglia independent) in glutamatergic neurons after RSD enhanced neuronal reactivity and fear memory.

The role of interleukin‐1 (IL‐1), a pro‐inflammatory cytokine, in parturition is typically noted by changes in its concentrations. Studying the expression of its receptor family, IL‐1 receptor (IL‐1R) 1, IL‐1R2, IL‐1R accessory protein (IL‐1RAcP), and its predominantly brain isoform, IL‐1RAcPb, during late gestation in the uterus in the Long‐Evans rat is another. We assessed changes in their mRNA and protein relative abundance in the uterus and compared IL‐1RAcP and IL‐1RAcPb mRNA abundance in uterus, cervix, ovaries, placenta, and whole blood of Long‐Evans rats during late gestation or in RU486 and progesterone‐treated dams using quantitative real‐time PCR and western immunoblotting. IL‐1R1, IL‐1RAcP, and IL‐1RAcPb mRNA abundance significantly increased in the uterus at delivery whereas IL‐1R2 mRNA abundance significantly decreased. IL‐1R1 protein increased at term and IL‐1R2 protein decreased at term compared to nonpregnant uteri. IL1‐RAcPb mRNA abundance was less than IL‐1RAcP, but in the lower uterine segment it was the highest of all tissues examined. RU486 stimulated preterm delivery and an increase in IL‐1R1 mRNA abundance whereas progesterone administration extended pregnancy and suppressed the increase in IL‐1R1. These data suggest that changes in uterine sensitivity to IL‐1 occur during late gestation and suggest another level of regulation for the control of delivery. The roles for IL‐1RAcP and IL‐1RAcPb need to be determined, but may relate to different intracellular signaling pathways. IL‐1R1 (A), IL‐1RAcP (C), and IL‐1RAcPb (D) mRNA abundance significantly increased in the rat uterus at delivery, whereas IL‐1R2 (B) mRNA abundance significantly decreased. Changes in uterine sensitivity to IL‐1 occur during late gestation and suggest another level of regulation for the control of delivery.

Interleukin-1 (IL-1) is a primary cytokine of innate immunity and inflammation. IL-1 belongs to a complex family including ligands with agonist activity, receptor antagonists, and an anti-inflammatory cytokine. The receptors for these ligands, the IL-1 Receptor (IL-1R) family, include signaling receptor complexes, decoy receptors, and negative regulators. Agonists and regulatory molecules co-evolved, suggesting the evolutionary relevance of a tight control of inflammatory responses, which ensures a balance between amplification of innate immunity and uncontrolled inflammation. IL-1 family members interact with innate immunity cells promoting innate immunity, as well as with innate and adaptive lymphoid cells, contributing to their differentiation and functional polarization and plasticity. Here we will review the properties of two key regulatory receptors of the IL-1 system, IL-1R2, the first decoy receptor identified, and IL-1R8, a pleiotropic regulator of different IL-1 family members and co-receptor for IL-37, the anti-inflammatory member of the IL-1 family. Their complex impact in pathology, ranging from infections and inflammatory responses, to cancer and neurologic disorders, as well as clinical implications and potential therapeutic exploitation will be presented.

Toll‐like receptors transduce their signals through the adaptor molecule MyD88 and members of the IL‐1R‐associated kinase family (IRAK‐1, 2, M and 4). IRAK‐1 and IRAK‐2, known to form Myddosomes with MyD88–IRAK‐4, mediate TLR7‐induced TAK1‐dependent NFκB activation. IRAK‐M was previously known to function as a negative regulator that prevents the dissociation of IRAKs from MyD88, thereby inhibiting downstream signalling. However, we now found that IRAK‐M was also able to interact with MyD88–IRAK‐4 to form IRAK‐M Myddosome to mediate TLR7‐induced MEKK3‐dependent second wave NFκB activation, which is uncoupled from post‐transcriptional regulation. As a result, the IRAK‐M‐dependent pathway only induced expression of genes that are not regulated at the post‐transcriptional levels (including inhibitory molecules SOCS1, SHIP1, A20 and IκBα), exerting an overall inhibitory effect on inflammatory response. On the other hand, through interaction with IRAK‐2, IRAK‐M inhibited TLR7‐mediated production of cytokines and chemokines at translational levels. Taken together, IRAK‐M mediates TLR7‐induced MEKK3‐dependent second wave NFκB activation to produce inhibitory molecules as a negative feedback for the pathway, while exerting inhibitory effect on translational control of cytokines and chemokines. IRAK‐M was reported to inhibit TLR signalling. Now, IRAK‐M is shown to activate NFκB via interaction with MyD88/IRAK‐4 leading to the induction of a negative feedback loop that limits the inflammatory response.

The Toll-interleukin 1 receptor superfamily includes the genes interleukin 1 receptor-like 1 ( IL1RL1 ), Toll like receptors ( TLRs ), myeloid differentiation primary-response 88 ( MyD88 ), and MyD88 adaptor-like ( TIRAP ). This study describes the interaction between MyD88, TIRAP and IL1RL1 against Helicobacter pylori infection. Cases and controls were genotyped at the polymorphic sites MyD88 rs6853, TIRAP rs8177374 and IL1RL1 rs11123923. The results show that specific combinations of IL1RL1 - TIRAP (AA-CT; P: 2,8 × 10 –17 ) and MyD88 - TIRAP - IL1RL1 (AA-CT-AA; P: 1,4 × 10 –8 ) – but not MyD88 alone—act synergistically against Helicobacter pylori. Nuclear magnetic resonance (NMR) clearly discriminates cases from controls by highlighting significantly different expression levels of several metabolites (tyrosine, tryptophan, phenylalanine, branched-chain amino acids, short chain fatty acids, glucose, sucrose, urea, etc.). NMR also identifies the following dysregulated metabolic pathways associated to Helicobacter pylori infection: phenylalanine and tyrosine metabolism, pterine biosynthesis, starch and sucrose metabolism, and galactose metabolism. Furthermore, NMR discriminates between the cases heterozygous at the  IL1RL1 locus from those homozygous at the same locus. Heterozygous patients are characterized by high levels of lactate, and IL1RL1 —both associated with anti-inflammatory activity—and low levels of the pro-inflammatory molecules IL-1β, TNF-α, COX-2, and IL-6.