CD14 Protein Acts as an Adaptor Molecule for the Immune Recognition of Salmonella Curli Fibers

Rapsinski, Glenn J.; Newman, Tiffanny; Oppong, Gertrude O.; Putten, Jos P. M. van; Tükel, Çaǧla

doi:10.1074/jbc.m112.447060

Cited by 45 publications

(41 citation statements)

References 89 publications

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“…1A). Curli also induced IL-6 production by BMDMs, as reported previously (36,41). LPS caused robust secretion of IL-6, likely through the activation of TLR4 (Fig.…”

Section: Curli Fibers Induce Secretion Of Il-1␤supporting

confidence: 54%

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Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

et al. 2015

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bAmyloids are proteins with cross-␤-sheet structure that contribute to pathology and inflammation in complex human diseases, including Alzheimer's disease, Parkinson's disease, type II diabetes, and secondary amyloidosis. Bacteria also produce amyloids as a component of their extracellular matrix during biofilm formation. Recently, several human amyloids were shown to activate the NLRP3 inflammasome, leading to the activation of caspase 1 and production of interleukin 1␤ (IL-1␤). In this study, we investigated the activation of the NLRP3 inflammasome by bacterial amyloids using curli fibers, produced by Salmonella enterica serovar Typhimurium and Escherichia coli. Here, we show that curli fibers activate the NLRP3 inflammasome, leading to the production of IL-1␤ via caspase 1 activation. Investigation of the underlying mechanism revealed that activation of Toll-like receptor 2 (TLR2) by curli fibers is critical in the generation of IL-1␤. Interestingly, activation of the NLRP3 inflammasome by curli fibers or by amyloid ␤ of Alzheimer's disease does not cause cell death in macrophages. Overall, these data identify a cross talk between TLR2 and NLRP3 in response to the bacterial amyloid curli and generation of IL-1␤ as a product of this interaction.A myloid proteins are produced by both bacteria and humans. In humans, more than 60 amyloidogenic proteins are produced throughout the body (1). Amyloids accumulate, forming deposits, during several complex diseases, such as Alzheimer's disease (AD), Parkinson's disease, type II diabetes, and secondary amyloidosis. Although it was initially thought that amyloids were only misfolded proteins causing disease pathology, it is becoming more apparent that the proteins have a function in the human body (2, 3). For instance, Pmel17, involved in melanin production, prevents melanocyte cytotoxicity (4-6), and secretory hormones in the endocrine system are stored in a cross-beta-sheetrich structure in secretory granules (7). Furthermore, it has recently been proposed that the amyloid ␤ peptide, found in the senile plaques of Alzheimer's disease patients, binds specific DNA regions and participates in gene regulation (8).Bacteria produce amyloids as a component of their extracellular matrix (ECM) to build multicellular communities termed biofilms (9). Biofilms are characterized by their resistant nature in response to environmental insults, including chemical treatments, antibiotics, and the immune system (10). It is thought that the amyloids act as a shield to protect bacteria in biofilms due to their highly resistant nature against chemicals and proteolytic enzymes. Although it is estimated that up to 40% of bacterial species produce amyloids in their biofilms (11), most of these proteins remain uncharacterized. Curli fibers, amyloids produced in the biofilms of Escherichia coli and Salmonella enterica serovar Typhimurium, are the most studied bacterial amyloid to date. Curli fibers are encoded by the csg gene cluster formed by two operons, csgBAC and csgDEFG (12-14). CsgA, the ...

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“…1A). Curli also induced IL-6 production by BMDMs, as reported previously (36,41). LPS caused robust secretion of IL-6, likely through the activation of TLR4 (Fig.…”

Section: Curli Fibers Induce Secretion Of Il-1␤supporting

confidence: 54%

“…Amyloid polymerization was conducted as previously described (36). One milligram of human amyloid ␤ 1-42 was dissolved in 400 l of HFIP.…”

Section: Methodsmentioning

confidence: 99%

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

et al. 2015

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“…Other membrane-bound co-receptors such as CD14 partner with the TLRs to enhance ligand recognition (36). CD14 interacts with A␤ (37) and curli fibrils (38) but is not required for NF-B activation by lysozyme (12), serum amyloid A (10), or (as we have shown here) IAPP. Multiple diseases of protein aggregation are also associated with activation of NLRP3 (29).…”

Section: Discussionmentioning

confidence: 99%

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Westwell‐Roper¹,

Denroche

Ehses

et al. 2016

Journal of Biological Chemistry

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Aggregation of islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction in type 2 diabetes and islet transplantation. Like other amyloidogenic peptides, human IAPP induces macrophage IL-1␤ secretion by stimulating both the synthesis and processing of proIL-1␤, a pro-inflammatory cytokine that (when chronically elevated) impairs beta cell insulin secretion. We sought to determine the specific mechanism of IAPP-induced proIL-1␤ synthesis. Soluble IAPP species produced early during IAPP aggregation provided a Toll-like-receptor-2-(TLR2-) dependent stimulus for NF-B activation in HEK 293 cells and bone marrow-derived macrophages (BMDMs). Nonamyloidogenic rodent IAPP and thioflavin-T-positive fibrillar amyloid produced by human IAPP aggregation failed to activate TLR2. Blockade of TLR6 but not TLR1 prevented hIAPP-induced TLR2 activation, consistent with stimulation of a TLR2/6 heterodimer. TLR2 and its downstream adaptor protein MyD88 were required for IAPP-induced cytokine production by BMDMs, a process that is partially dependent on autoinduction by IL-1. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1␤ secretion, whereas late IAPP aggregates induced NLRP3-dependent IL-1␤ secretion by LPS-primed macrophages. Moreover, inhibition of TLR2 and depletion of islet macrophages prevented up-regulation of Il1b and Tnf expression in human IAPP-expressing transgenic mouse islets. These data suggest participation by both soluble and fibrillar aggregates in IAPPinduced islet inflammation. IAPP-induced activation of TLR2 and secretion of IL-1 may be important therapeutic targets to prevent amyloid-associated beta cell dysfunction.

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“…CD14 can interact with TLR2 to form two different heterocomplexes. The first complex, composed of CD14-TLR2-TLR1, is implicated in the recognition of triacylated lipoproteins (Manukyan et al, 2005;Nakata et al, 2006;Triantafilou et al, 2006) and Salmonella amyloid curli fibers (Rapsinski et al, 2013) (Fig. 2).…”

Section: Cd14-dependent Recognition Of Non-endotoxin Ligandsmentioning

confidence: 99%

Toll-like receptor co-receptors as master regulators of the immune response

Gioia

Zanoni

2015

Molecular Immunology

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CD14 Protein Acts as an Adaptor Molecule for the Immune Recognition of Salmonella Curli Fibers

Cited by 45 publications

References 89 publications

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

Toll-Like Receptor 2 and NLRP3 Cooperate To Recognize a Functional Bacterial Amyloid, Curli

Differential Activation of Innate Immune Pathways by Distinct Islet Amyloid Polypeptide (IAPP) Aggregates

Toll-like receptor co-receptors as master regulators of the immune response

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