Loose lipid rafts lead to trigger-happy mast cells

Abstract

Mast cells that accumulate cholesterol precursors in their membranes tend to overreact, according to Kovarova and colleagues on page 1161. This mast cell hyperresponsiveness might help explain why patients with a genetic disease known as Smith-Lemli-Opitz syndrome (SLOS) are prone to food allergies. Figure 1 Degranulation is enhanced in mast cells lacking the enzyme that reduces 7-dehydrocholesterol (DHCR KO). Patients with SLOS have abnormally low levels of circulating cholesterol—and a corresponding abundance of the cholesterol precursor 7-dehydrocholesterol (DHC)—due to defects in the gene that encodes the DHC-reducing enzyme (DHCR7). This cholesterol deficiency causes a bevy of developmental defects, consistent with the known requirement for cholesterol during embryonic development. But the allergic manifestations of SLOS are poorly understood. Kovarova and colleagues suspected that mast cells—the principle allergy-triggering cell type—might be involved, as mast cells rely on the proper distribution of cholesterol-rich lipid rafts in their membranes for appropriate activation and deactivation. Their hunch was right. Mast cells from Dhcr7-deficient mice were hyperactive compared with wild-type cells, as measured by increased degranulation and proinflammatory cytokine production upon activation. But to their surprise, the deficient cells had normal numbers of lipid rafts—although the abundance of DHC and paucity of cholesterol made the rafts less stable than normal. The destabilized rafts contained fewer molecules of the kinase Lyn, leading to a decrease in the Lyn-dependent activation of Csk-binding protein, a negative regulator of the degranulation-stimulating kinase Fyn. Depleting wild-type cells of cholesterol had the same activation-enhancing effect, which was reversed when cholesterol was added back. But adding cholesterol to the Dhcr7-deficient cells had minimal effect, suggesting that the activation defect was caused by the accumulation of DHC, rather than the depletion of cholesterol. These results suggest that patients with other diseases involving defects in cholesterol biosynthesis might be more prone to allergies—a possibility that remains to be tested.