Silica increases cytosolic free calcium ion concentration of alveolar macrophages in vitro.

Rat alveolar macrophages were exposed to silica dust (quartz) suspended in culture medium (SiO2, dry particle size less than 5 microns in diameter) and fluctuation in their cytosolic free calcium content ([Ca2+]i) was detected in cell monolayers with a fluorescent calcium probe (Indo-1AM). Cytosolic free calcium content was correlated with lactate dehydrogenase (LDH) release, an index of cell damage. SiO2 induced a concentration- and time-dependent increase of cytosolic free Ca2+ ion concentration and LDH release. [Ca2+]i was increased about fivefold when cells were exposed to 200 micrograms of SiO2 per milliliter (3 ml per dish) for 2 hr. [Ca2+]i changed within 15 min of SiO2 treatment, whereas LDH release was measurably increased only after 30 min. Chelation of extracellular Ca2+ by 2 mM ethylene glycol bis(beta-aminoethyl ether) N,N'-tetraacetate did not prevent SiO2-induced fluctuation of macrophage [Ca2+]i, but did partially prevent the SiO2-induced increase in LDH release (p less than 0.01). We conclude that a very early event in SiO2-induced damage of alveolar macrophages involves mobilization of intracellular calcium pools to increase [Ca2+]i. These results suggest that SiO2-induced macrophage damage, a key event in the development of silicosis, may involve perturbation of intracellular calcium homeostasis.     

Metabolic pathways in T cell fate and function

T cell growth and function must be tightly regulated to provide protection against foreign pathogens, while avoiding autoimmunity and immunodeficiency. It is now apparent that T cell metabolism is highly dynamic and has a tremendous impact on the ability of T cells to grow, activate and differentiate. Specific metabolic pathways provide energy and biosynthetic precursors that must support specific cell functions, as effector, regulatory, memory, and alloreactive T cells have distinct metabolic needs in immunity and inflammation. Here, we review the signaling pathways that control metabolism and how the metabolic phenotypes of T cell subtypes integrate with T cell function. Ultimately, these metabolic differences may provide new opportunities to modulate the immune response and treat inflammatory and autoimmune diseases.     

Leptin directly promotes T‐cell glycolytic metabolism to drive effector T‐cell differentiation in a mouse model of autoimmunity

Upon activation, T cells require energy for growth, proliferation, and function. Effector T (Teff) cells, such as Th1 and Th17 cells, utilize high levels of glycolytic metabolism to fuel proliferation and function. In contrast, Treg cells require oxidative metabolism to fuel suppressive function. It remains unknown how Teff/Treg‐cell metabolism is altered when nutrients are limited and leptin levels are low. We therefore examined the role of malnutrition and associated hypoleptinemia on Teff versus Treg cells. We found that both malnutrition‐associated hypoleptinemia and T cell‐specific leptin receptor knockout suppressed Teff‐cell number, function, and glucose metabolism, but did not alter Treg‐cell metabolism or suppressive function. Using the autoimmune mouse model EAE, we confirmed that fasting‐induced hypoleptinemia altered Teff‐cell, but not Treg‐cell, glucose metabolism, and function in vivo, leading to decreased disease severity. To explore potential mechanisms, we examined HIF‐1α, a key regulator of Th17 differentiation and Teff‐cell glucose metabolism, and found HIF‐1α expression was decreased in T cell‐specific leptin receptor knockout Th17 cells, and in Teff cells from fasted EAE mice, but was unchanged in Treg cells. Altogether, these data demonstrate a selective, cell‐intrinsic requirement for leptin to upregulate glucose metabolism and maintain function in Teff, but not Treg cells.