Thapsigargin, which induces ER stress by blocking ER SERCA pumps and thereby depleting ER Ca 2+ stores, also led to IL-1 β secretion, although exclusively in primary cells ( Figure 1a and data not shown). Similarly, induction of ER stress using Brefeldin A (BFA), which reversibly blocks protein transport from the ER to the Golgi, also caused IL-1 β maturation and secretion. The presence of processed IL-1 β was detected in the supernatant of the human monocytic cell line THP-1 and primary human monocytes – macrophages following stimulation with tunicamycin ( Figures 1a and b). Human macrophages were exposed to tunicamycin, an inhibitor of GlcNAc-1-phosphate transferase and thus of glycoprotein synthesis, in order to induce ER stress. We first determined whether induction of ER stress triggers the maturation of IL-1 β. 4 As the mechanism by which ER stress triggers inflammation remains poorly understood, we sought to investigate the role of the NLRP3 inflammasome as a potential sensor of ER stress. 6 In addition to microbial and viral danger signals (PAMPs), the NLRP3 inflammasome is unique in that it can sense the presence of endogenous danger signals that are associated with cellular or tissue damage or stress (DAMPs), such as uric acid crystals. Of the thus far described inflammasomes, the NLRP3 inflammasome is most fully characterized. 4, 5 Some of these NLRs participate in multiprotein complexes termed inflammasomes, which mediate caspase-1-dependent maturation of the highly proinflammatory cytokine interleukin-1 β (IL-1 β). In particular, proteins belonging to the NOD-like receptor (NLR) family have been identified as central players in innate immunity. Recent years have seen remarkable growth in our understanding of the cellular and molecular mechanisms that control the inflammatory response.
In addition to the intracellular responses, chronic ER stress can also, by mechanisms that remain poorly characterized, cause inflammation within affected tissues. This response is initially aimed at altering the cellular transcriptional and translational programs to resolve the protein-folding defect, but if the problem persists it initiates programed cell death. 2 Under such conditions, the ER initiates the unfolded protein response (UPR). The inflammatory response is frequently triggered as a consequence of ER stress, caused by metabolic problems or by the accumulation of misfolded proteins.
1 The endoplasmic reticulum (ER) stress response is a potent, evolutionarily conserved response to misfolded proteins and cellular metabolic stress.
Prolonged or chronic inflammation, however, can exacerbate tissue damage and is implicated in the development of diseases, such as arthritis, neurodegenerative diseases and type 2 diabetes. Inflammation is the first response of the immune system to infection or tissue injury, and is meant to protect the body from these insults.
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