Lipid body accumulation alters calcium signaling dynamics in immune cells

Abstract

Summary There is well-established variability in the numbers of lipid bodies (LB) in macrophages, eosinophils, and neutrophils. Similarly to the steatosis observed in adipocytes and hepatocytes during hyperinsulinemia and nutrient overload, immune cell LB hyper-accumulate in response to bacterial and parasitic infection and inflammatory presentations. Recently we described that hyperinsulinemia, both in vitro and in vivo, drives steatosis and phenotypic changes in primary and transformed mast cells and basophils. LB reach high numbers in these steatotic cytosols, and here we propose that they could dramatically impact the transcytoplasmic signaling pathways. We compared calcium release and influx responses at the population and single cell level in normal and steatotic model mast cells. At the population level, all aspects of FcεRI-dependent calcium mobilization, as well as activation of calcium-dependent downstream signalling targets such as NFATC1 phosphorylation are suppressed. At the single cell level, we demonstrate that LB are both sources and sinks of calcium following FcεRI cross-linking. Unbiased analysis of the impact of the presence of LB on the rate of trans-cytoplasmic calcium signals suggest that LB enrichment accelerates calcium propagation, which may reflect a Bernoulli effect. LB abundance thus impacts this fundamental signalling pathway and its downstream targets.

Insulin-induced lipid body accumulation is accompanied by lipid remodelling in model mast cells

“…In the populations of cells used here, at least 80% of the cells were confirmed (by Oil Red O staining and microscopy) to have gained significant lipid body accumulation and exhibit a 'steatotic' staining pattern by the 6-d insulin exposure timepoint (Figure 1(e)). These data are consistent with both our prior studies and observations from adipocyte and immunocytes systems that see lipid body accumulation and overall gains in lipid content in response to insulin, nutrient excess and infection, respectively [6][7][8][9][31][32][33].…”

“…Chronic insulin elevation has functional consequences for numerous cells, tissues and organs in the body, including those of the immune system [3][4][5]. We have previously shown that chronic insulin elevation alters mast cell functional phenotypes in vitro, and there is in vivo and clinical evidence that altered levels of insulin affect the outcomes of allergic and anaphylactic inflammatory responses [6][7][8][9]. Chronic insulin exposure quantitatively alters the lipid content of mast cells, causes a steatosis-like accumulation of lipid bodies similar to that observed in neutrophils and macrophages under conditions of infection.…”

“…In prior studies we have shown that chronic insulin exposure is associated with elevated lipid body numbers, overall increases in cellular lipid content and elevated leukotriene C4 (LTC4) production in model mast cells [6][7][8][9]27]. In the current study, we use a similar model system in which a mucosal mast cell-like line is exposed to elevated insulin over a chronic time period.…”

Calcium Homeostasis Disruption - a Bridge Connecting Cadmium-Induced Apoptosis, Autophagy and Tumorigenesis

“…The increasing ratio of PC and PE or increasing PC content in a membrane can inhibit the calcium transport activity of SERCA. With the inhibited protein expressions of SERCA2A and SERCA2B, the release process of Ca 2+ stored in the ER is inhibited [20]. These results indicate that cadmium not only directly inhibits calcium channels or proteins, and thus influences calcium homeostasis, but also affects calcium homeostasis in an indirect way through cadmium-induced lipid metabolism disturbance.…”

Chloroquine Inhibits Ca2+ Signaling in Murine CD4+ Thymocytes

“…Phosphorylated PLC then breaks down phosphatidylinositol-4,5-bisphosphate (PIP 2 ) into two components: inositol-1,4,5-trisphosphate (IP 3 ) and diacylglycerol [11,12]. IP 3 binds to its receptor (IP 3 R), which is located on the surface of the endoplasmic reticulum (ER).…”