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Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.

ABSTRACT: Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (? 2M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). ? 2M is best known for its remarkable ability to inhibit a broad spectrum of proteases, but the full gamut of its activities affects diverse biological processes. For example, ? 2M can stabilise and facilitate the clearance of the Alzheimer's disease-associated amyloid beta (A?) peptide. Additionally, ? 2M can influence the signalling of cytokines and growth factors including neurotrophins. The results of several studies support the idea that the functions of ? 2M are uniquely regulated by hypochlorite, an oxidant that is generated during inflammation, which induces the native ? 2M tetramer to dissociate into dimers. This review will discuss the evidence for hypochlorite-induced regulation of ? 2M and the possible implications of this in neuroinflammation and neurodegeneration.

SUBMITTER: Cater JH

PROVIDER: S-EPMC6679887 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.

Cater Jordan H JH Wilson Mark R MR Wyatt Amy R AR

Oxidative medicine and cellular longevity 20190722

Alpha-macroglobulins are ancient proteins that include monomeric, dimeric, and tetrameric family members. In humans, and many other mammals, the predominant alpha-macroglobulin is alpha-2-macroglobulin (α 2M), a tetrameric protein that is constitutively abundant in biological fluids (e.g., blood plasma, cerebral spinal fluid, synovial fluid, ocular fluid, and interstitial fluid). α 2M is best known for its remarkable ability to inhibit a broad spectrum of prot ...[more]

PMID: 31428227

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Project description:For patients with non-cirrhotic liver-based metabolic disorders, hepatocyte transplantation can be an effective treatment. However, long-term function of transplanted hepatocytes following infusion has not been achieved due to insufficient numbers of hepatocytes reaching the liver cell plates caused by activation of the instant blood-mediated inflammatory reaction (IBMIR). Our aim was to determine if the natural immune modulator, alpha-1 antitrypsin (AAT), could improve engraftment of transplanted hepatocytes and investigate its mechanism of action. A tubing loop model was used to analyse activation of the IBMIR when human hepatocytes were in contact with ABO-matched blood and 4 mg/ml AAT. Platelet and white cell counts, complement and cytokine expression were analysed. To determine if AAT could improve short-term engraftment, female rats underwent tail vein injection of AAT (120 mg/kg) or water (control) prior to the intrasplenic transplantation of 2 × 107 male hepatocytes. At 48 h and 1 week, livers were collected for analysis. In our loop model, human hepatocytes elicited a significant drop in platelet count with thrombus formation compared to controls. Loops containing AAT and hepatocytes showed no platelet consumption and no thrombus formation. Further, AAT treatment resulted in reduced IL-1β, IL-6 and IFN-γ and increased IL-1RA compared to untreated loops. In vivo, AAT significantly improved engraftment of rat hepatocytes compared to untreated at 48 h. AAT infusion may inhibit the IBMIR, thus improving short-term engraftment of donor hepatocytes and potentially improve the outcomes for patients with liver-based metabolic disease. KEY MESSAGES: • Alpha-1 antitrypsin (AAT) acts as an immune modulator to improve the efficacy of hepatocyte transplantation. • Treatment with AAT decreased thrombus formation and pro-inflammatory cytokine expression in a tubing loop model. • AAT significantly improved engraftment of donor hepatocytes within the first 48 h post transplantation.

Dataset Information

Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.

Publications

Alpha-2-Macroglobulin, a Hypochlorite-Regulated Chaperone and Immune System Modulator.

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