IAPP/amylin deposition, which is correlated with expressions of ASC and IL-1β in β-cells of Langerhans’ islets, directly initiates NLRP3 inflammasome activation

Abstract

Recent findings revealed that type 2 diabetes mellitus (T2D) is a chronic inflammatory disease and an islet amyloid polypeptide (IAPP)/amylin, is deposited within pancreatic islets. IAPP/amylin has been reported to activate NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in infiltrated macrophages. NLRP3, an intracellular pattern recognition receptor, has been shown to recognize pathogens and/or metabolites and complexes with the adopter protein apoptosis-associated speck-like protein containing a caspase-recruitment domain ASC to form a huge complex, called an inflammasome, an interleukin (IL)-1β-processing platform. Although reactive oxygen species (ROS) were reported to be involved in activation of NLRP3 inflammasome, we were hypothesized that IAPP could directly activate NLRP3 inflammasome, leading to islets β-cell death. We analyzed expression of the inflammasome components ASC, NLRP3, caspase-1, IL-1β, IAPP/amylin, and insulin immunohistochemically in Langerhans’ islets of autopsy cases. The initial event of NLRP3 inflammasome activation was assessed using a cell-free system consisting of NLRP3 and ASC with the amplified luminescent proximity homogeneous assay. IAPP/amylin deposition in Langerhans’ islets was detected and significantly correlated with expressions of IL-1β and ASC. IAPP/amylin directly interacted with NLRP3 and initiated an interaction between NLRP3 and ASC in a cell-free system. The deposition of IAPP/amylin in β-cells of Langerhans’ islets may act together with the expression level of an inflammasome component, ASC, to regulate IL-1β processing, and directly lead to the dysfunction of β-cells. The interaction between IAPP/amylin and NLRP3 could be an attractive drug target to avoid both inflammation and β-cell death for T2D therapy.

The Human Host‐Defense Peptide Cathelicidin LL‐37 is a Nanomolar Inhibitor of Amyloid Self‐Assembly of Islet Amyloid Polypeptide (IAPP)

“…Our results suggest that the inhibitor function of LL‐37 is mediated by binding to 1) early prefibrillar IAPP species and their sequestration into soluble, non‐fibrillar hetero‐assemblies and 2) IAPP fibrils and their conversion into seeding‐incompetent assemblies. Together with findings by others, our results support the hypothesis that LL‐37 secreted by pancreatic β‐cells or infiltrated neutrophils under conditions of pancreatic inflammation binds IAPP and suppresses its amyloid self‐assembly and related β‐cell damage, thus slowing down T2D pathogenesis (Scheme ) . Studies on the potential physiological relevance of the LL‐37/IAPP interaction are now of high priority.…”

Harnessing the Activation of Toll-Like Receptor 2/6 by Self-Assembled Cross-β Fibrils to Design Adjuvanted Nanovaccines

“…Besides, TLR engagement resulting in the activation of the transcription factor NF-kB, acts as a first priming signal of the inflammasome by the upregulation of NLRP3 [ 54 , 55 ]. Thus, considering that some studies have shown that cross-β fibrils derived from the amyloid β-peptide [ 56 ] and IAPP [ 57 , 58 ] can activate the NLRP3 inflammasome, the stimulation of TLR2/6 by M2e-NFs could also result on inflammasome priming, a hypothesis that will need to be further investigated.…”

The role of interleukin-1 in general pathology

“…Another oligomer of amyloid, amyloid β, can induce IL-1β via NLRP3 inflammasomes in a process involving the phagocytosis of amyloid β in glial cells in patients with Alzheimer’s disease (AD) and subsequent lysosomal damage and release of cathepsin B [108]. ROS are considered to be involved in the activation of NLRP3 inflammasomes, and it was suggested that direct interaction between amyloidogenic peptide and NLRP3 could initiate NLRP3 inflammasome formation in a cell-free system [109, 110]. Both IL-1α and IL-1β gene polymorphisms have been reported to be associated with central obesity and metabolic syndrome in a population with coronary heart disease in an epidemiologic study [111].…”