Acute activation of SERCA with CDN1163 attenuates IgE‐mediated mast cell activation through selective impairment of ROS and p38 signaling

Abstract

Mast cells are granulocytic immune sentinels present in vascularized tissues that drive chronic inflammatory mechanisms characteristic of allergic pathologies. IgE‐mediated mast cell activation leads to a rapid mobilization of Ca2+ from intracellular stores, which is essential for the release of preformed mediators via degranulation and de novo synthesized proinflammatory cytokines and chemokines. Given its potent signaling capacity, the dynamics of Ca2+ localization are highly regulated by various pumps and channels controlling cytosolic Ca2+ concentrations. Among these is sarco/endoplasmic reticulum Ca2+‐ATPase (SERCA), which functions to maintain low cytosolic Ca2+ concentrations by actively transporting cytosolic Ca2+ ions into the endoplasmic reticulum. In this study, we characterized the role of SERCA in allergen‐activated mast cells using IgE‐sensitized bone marrow‐derived mast cells (BMMCs) treated with the SERCA activating compound, CDN1163, and simultaneously stimulated with allergen through FcεRI under stem cell factor (SCF) potentiation. Acute treatment with CDN1163 was found to attenuate early phase mast cell degranulation along with reactive oxygen species (ROS) production. Additionally, treatment with CDN1163 significantly reduced secretion of IL‐6, IL‐13, and CCL3, suggesting a role for SERCA in the late phase mast cell response. The protective effects of SERCA activation via CDN1163 treatment on the early and late phase mast cell response may be driven by the selective suppression of p38 MAPK signaling. Together, these findings implicate SERCA as an important regulator of the mast cell response to allergen and suggest SERCA activity may offer therapeutic potential targeting allergic pathologies, warranting further investigation.

The Effect of SERCA Activation on Functional Characteristics and Signaling of Rat Soleus Muscle upon 7 Days of Unloading

“…In this study, treatment with CDN1163 prevented an increase in oxidized tropomyosin in unloaded muscle. The data on oxidized tropomyosin presented in the current study correlated well with the previously reported CDN1163-induced decrease in oxidative stress in the muscle of Sod1 −/− mice [27] and in mast cells [64]. It was reported that changes in the tropomyosin oxidation in unloaded muscle can modify the sensitivity to calcium and the ability of myofilaments to generate maximum force [61].…”

Mast Cells as a Potential Target of Molecular Hydrogen in Regulating the Local Tissue Microenvironment

“…ROS have the potential to modify and activate MC secretory activity is well known [22][23][24][25][26][27][28][29][30][31][32]. Under oxidative stress, MCs become an essential structural and functional component, and the regulation of this component can affect the integral state of the local tissue microenvironment and its resistance to various challenges.…”

“…MCs are of special significance in the development of a pro-inflammatory background, regulating the state of numerous cells of the immune and stromal landscape, and the extracellular matrix of connective tissue [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. ROS have the potential to modify and activate MC secretory activity is well known [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. Under oxidative stress, MCs become an essential structural and functional component, and the regulation of this component can affect the integral state of the local tissue microenvironment and its resistance to various challenges.…”