Autocrine abscisic acid plays a key role in quartz‐induced macrophage activation

Abstract

Inhalation of quartz induces silicosis, a lung disease where alveolar macrophages release inflammatory mediators, including prostaglandin-E(2) (PGE(2)) and tumor necrosis factor α (TNF-α). Here we report the pivotal role of abscisic acid (ABA), a recently discovered human inflammatory hormone, in silica-induced activation of murine RAW264.7 macrophages and of rat alveolar macrophages (AMs). Stimulation of both RAW264.7 cells and AMs with quartz induced a significant increase of ABA release (5- and 10-fold, respectively), compared to untreated cells. In RAW264.7 cells, autocrine ABA released after quartz stimulation sequentially activates the plasma membrane receptor LANCL2 and NADPH oxidase, generating a Ca(2+) influx resulting in NFκ B nuclear translocation and PGE(2) and TNF-α release (3-, 2-, and 3.5-fold increase, respectively, compared to control, unstimulated cells). Quartz-stimulated RAW264.7 cells silenced for LANCL2 or preincubated with a monoclonal antibody against ABA show an almost complete inhibition of NFκ B nuclear translocation and PGE(2) and TNF-α release compared to controls electroporated with a scramble oligonucleotide or preincubated with an unrelated antibody. AMs showed similar early and late ABA-induced responses as RAW264.7 cells. These findings identify ABA and LANCL2 as key mediators in quartz-induced inflammation, providing possible new targets for antisilicotic therapy.

Microgram amounts of abscisic acid in fruit extracts improve glucose tolerance and reduce insulinemia in rats and in humans

“…Another question that should be investigated further is the possibility that ABA at a dose of approximately 1 mg/kg lacks the proinflammatory effects that are observed in vitro at low micromolar hormone concentrations (3)(4)(5). The stimulation by micromolar ABA of the activation of innate immune cells observed in vitro with 1-10 mM ABA (3-5) may not occur in vivo after administration of microgram amounts of ABA, resulting in ABAp levels on the order of tens of nanomoles per liter.…”

“…Chemical or physical stimuli induce ABA release from human granulocytes, and ABA in turn stimulates phagocytosis, cell migration, and production of reactive oxygen species (3). Activated platelets or quartz particles stimulate ABA release from monocytes/macrophages and ABA, in an autocrine manner, stimulates release of cytokines and prostaglandin E2 (4,5). IL-8 induces human mesenchymal stem cells to release ABA, which stimulates the release of growth factors from these cells and colony growth from human hemopoietic progenitors (6,7).…”

Abscisic Acid: A New Mammalian Hormone Regulating Glucose Homeostasis

“…Blood-derived human monocytes release ABA when exposed to thrombin-activated platelets, a situation that occurs for instance at the injured vascular endothelium, and ABA acts as an autocrine and paracrine proinflammatory hormone: it stimulates monocyte migration and the release of monocyte chemoattractant protein-1 (MCP-1), prostaglandin E2 (PGE2) and metalloprotease-9 (MMP-9), as well as vascular smooth muscle cell migration and proliferation . Stimulation of rodent macrophages with quartz triggers ABA release and autocrine ABA stimulates ROS production and the release of PGE2 and of tumor necrosis factor-(TNF-, all key inflammatory mediators involved in the induction of silicosis, a chronic lung inflammatory disease [Magnone, 2012].…”

“…ABA sensing in mammalian innate immune cells, keratinocytes and -pancreatic cells requires the protein LANCL-2, as silencing of LANCL-2 by means of specific small interfering RNAs (siRNAs) abrogates the cell response to ABA Bruzzone, 2012a;Magnone, 2012]. Purified, recombinant LANCL2 indeed binds ABA, as detected using different experimental approaches, including saturation binding, scintillation proximity assays, dot blot experiments and affinity chromatography [Sturla, 2011].…”

Impaired Increase of Plasma Abscisic Acid in Response to Oral Glucose Load in Type 2 Diabetes and in Gestational Diabetes

“…Interestingly, ABA was found to play a conserved role as a “stress hormone” also in lower Metazoa, regulating animal responses to temperature and light [2, 3], and in mammals, regulating the activation of innate immune cells [4, 5] and glucose homeostasis [6–8]. …”