IL-1β is an important inflammatory mediator of type 2 diabetes (T2D). Here we show that oligomers of islet amyloid polypeptide (IAPP), a protein that forms amyloid deposits in the pancreas during T2D, trigger the Nlrp3 inflammasome and generate mature interleukin (IL)-1β. A T2D therapy, glyburide, suppresses IAPP-mediated IL-1β production in vitro. Processing of IL-1β initiated by IAPP first requires priming, a process that involves glucose metabolism and can be facilitated by minimally oxidized low density lipoprotein. Finally, mice transgenic for human IAPP have increased IL-1β in pancreatic islets, which colocalizes with amyloid and macrophages. Our findings reveal novel mechanisms in the pathogenesis of T2D and treatment of pathology caused by IAPP.

The recognition of microbial pathogens by the innate immune system involves Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns, with TLR-4 mediating the response to lipopolysaccharide from Gram-negative bacteria. All TLRs have a Toll/IL-1 receptor (TIR) domain, which is responsible for signal transduction. MyD88 is one such protein that contains a TIR domain. It acts as an adapter, being involved in TLR-2, TLR-4 and TLR-9 signalling; however, our understanding of how TLR-4 signals is incomplete. Here we describe a protein, Mal (MyD88-adapter-like), which joins MyD88 as a cytoplasmic TIR-domain-containing protein in the human genome. Mal activates NF-kappaB, Jun amino-terminal kinase and extracellular signal-regulated kinase-1 and -2. Mal can form homodimers and can also form heterodimers with MyD88. Activation of NF-kappaB by Mal requires IRAK-2, but not IRAK, whereas MyD88 requires both IRAKs. Mal associates with IRAK-2 by means of its TIR domain. A dominant negative form of Mal inhibits NF-kappaB, which is activated by TLR-4 or lipopolysaccharide, but it does not inhibit NF-kappaB activation by IL-1RI or IL-18R. Mal associates with TLR-4. Mal is therefore an adapter in TLR-4 signal transduction.

The Toll-interleukin 1 receptor (TIR) superfamily, defined by the presence of an intracellular TIR domain, initiates innate immunity through activation of the transcription factor NF-kappa B, leading to the production of proinflammatory cytokines. ST2 is a member of the TIR family that does not activate NF-kappa B and has been suggested as an important effector molecule of T helper type 2 (T(H)2) responses. We show here that the membrane-bound form of ST2 negatively regulated type I interleukin 1 receptor (IL-1RI) and Toll-like receptor 4 (TLR4) but not TLR3 signaling by sequestrating the adaptors MyD88 and Mal. In contrast to wild-type mice, ST2-deficient mice failed to develop endotoxin tolerance. Thus, these results provide a molecular explanation for the function of ST2 in T(H)2 responses, as inhibition of TLRs promotes a T(H)2 response, and also identify ST2 as a key regulator of endotoxin tolerance.

Toll-like receptors (TLRs) and members of their signalling pathway play an important role in the initiation of the innate immune response to a wide variety of pathogens1,2,3. The adaptor protein TIRAP mediates downstream signalling of 5,6. We report a case-control genetic association study of 6106 individuals from Gambia, Kenya, United Kingdom, and Vietnam, with invasive pneumococcal disease, bacteraemia, malaria and tuberculosis. Thirty-three SNPs were genotyped, including TIRAP S180L. Heterozygous carriage of this variant was found to associate independently with all four infectious diseases in the different study populations (P=0.003, OR=0.59, 95%CI 0.42-0.83 for IPD; P=0.003, OR=0.40, 95%CI 0.21-0.77 for bacteraemia; P=0.002, OR=0.47, 95%CI 0.28-0.76 for malaria; P=0.008, OR=0.23 95%CI 0.07-0.73 for tuberculosis). Substantial support for a protective effect of S180L heterozygosity against infectious diseases was observed when the study groups were combined (N=6106, OverallCorrespondence should be addressed on genetics to AVSH (adrian.hill@well.ox.ac.uk) In the UK population, heterozygosity at TIRAP S180L was associated with protection from invasive pneumococcal disease (3×2 χ 2 =8.72, P=0.013, Table 1). An excess of mutant homozygotes amongst IPD cases (Table 1) was also observed in this UK population. TIRAP S180L was then examined in a separate group of UK individuals with thoracic empyema and a second control group. Although no association was observed between genotype and susceptibility to thoracic empyema overall (n=584, 3×2 χ 2 =0.63, P=0.73), analysis of the small subgroup of individuals with pneumococcal empyema revealed a non-significant trend towards association (3×2 χ 2 =5.05, P=0.080; Table 1). Interestingly, an excess of mutant homozygotes was again observed amongst this second group of IPD cases (Table 1).We then studied TIRAP S180L in a second population with invasive bacterial disease, comprising Kenyan children with well-defined bacteraemia. Although the mutant allele was found to be less common in the Kenyan population than in UK individuals, the same pattern of association was observed. The TIRAP S180L heterozygotes were significantly more common amongst community controls (5.9%), compared to individuals with bacteraemia (2.4%) (2×2 χ 2 =9.05, P=0.003; Table 1). The heterozygote protective effect of the S180L locus was also significant within the subgroup of 164 Kenyan children with pneumococcal bacteraemia (F exact =0.024, Table 1), thus replicating the findings in the UK studies.In the Gambian malaria case-control study, TIRAP S180L heterozygosity demonstrated a significant protective effect against both general malaria (Wald=8.35, P=0.004, Table 1) and severe malaria (Wald=8.706, P=0.003, Table 1). This result was replicated in a second malaria case-control study, this time in a Vietnamese population whose design included only cases of severe malaria: TIRAP S180L heterozygotes were again found to be more prevalent Finally, the possible effect of the TIRAP S180L polymorphism on ...

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