IgE-dependent human basophil responses are inversely associated with the sarcoplasmic reticulum Ca2+-ATPase (SERCA)

Abstract

Basophils crucially contribute to allergies and other Th2-driven diseases by rapidly releasing inflammatory and immunomodulatory mediators following high-affinity IgE-receptor crosslinking. Although these basophil-mediated responses depend on sensitization with antigen-specific IgE, this does not necessarily predict clinical symptom severity. It is thought that the balance of early stimulatory (e.g. SYK) and inhibitory (e.g. SHIP-1) intracellular signals are associated with basophil responsiveness, which is also critically dependent on calcium mobilization. Previous studies suggest that the sarcoplasmic reticulum Ca2+-ATPase (SERCA2), which regulates cytosolic calcium levels, may be inversely associated with airway smooth muscle reactivity in asthma. Since basophils are implicated in asthma severity, our aims were to address whether SERCA2 is implicated in human basophil responses, especially following IgE-mediated activation. Human basophils were obtained from buffy coats, following research ethics approval, and further purified by immunomagnetic cell sorting. Expressions of SERCA2, and other isoforms, were determined by Western blotting in parallel to measuring IgE-dependent histamine releases from the same donors. The effects of a SERCA-activator and inhibitor were also assessed on their abilities to modulate basophil histamine release. We observed an inverse correlation between basophil responsiveness to IgE-dependent stimulation and SERCA2 expression. Thapsigargin, a highly-specific SERCA inhibitor, stimulated basophil histamine release and potentiated IgE-dependent secretion of the amine. Conversely, disulfiram, a SERCA activator, inhibited IgE-dependent basophil activation. The results obtained from this exploratory study indicate that SERCA2 may be an additional regulator of basophil reactivity alongside early excitatory or inhibitory signal transduction pathways.

OpiCa1-PEG-PLGA nanomicelles antagonize acute heart failure induced by the cocktail of epinephrine and caffeine

“…In addition to the two strategies of directly inhibiting sympathetic excitation by using β1 receptor blockers and reducing SR Ca 2+ reuptake by inhibiting phospholamben (PLN) phosphorylation and the over-activation of the Ca 2+ -ATPase SERCA, we used a novel kind of RyR targeting peptide ligand calcin to partially activate RyR2, so as to increase its open frequency and actively release the SR Ca 2+ , which is also a potential strategy to prevent excessive SR Ca 2+ elevation, and the feasibility of this strategy was confirmed on CPVT by using a representative Imperacalcin (also named as Imperatoxin A) in our previous studies [ [9] , [10] , [11] , [12] , [13] , [14] , [15] ]. Nevetheless, as a spherical peptide containing 33–35 amino acids, calcin has been found to mainly antagonize gentle PVCs or non-sustained BVTs rather than severe sustained BVTs or PVTs; like most of peptide drugs, calcin was also found to have a fast metabolic rate in vivo , of which the half-life is even less than 2 h, therefore, it is necessary to improve its drug efficacy by increasing the local concentration in heart, as well as to extend its action duration by controlled release through pharmaceutic methods [ 16 , 17 ].…”