Abstract
Orientia (O.) tsutsugamushi-induced scrub typhus is endemic across many regions of Asia and the Western Pacific, where an estimated 1 million cases occur each year; the majority of patients infected with O. tsutsugamushi end up with a cytokine storm from a severe inflammatory response. Previous reports have indicated that blocking tumor necrosis factor (TNF)-α reduced cell injury from a cytokine storm. Since TNF-α production is known to be associated with intracellular Ca2+ elevation, we examined the effect of store-operated Ca2+ entry (SOCE) inhibitors on TNF-α production in O. tsutsugamushi-infected macrophages. We found that 2-aminoethoxydiphenyl borate (2-APB), but not SKF96365, facilitates the suppression of Ca2+ mobilization via the interruption of Orai1 expression in O. tsutsugamushi-infected macrophages. Due to the decrease of Ca2+ elevation, the expression of TNF-α and its release from macrophages was repressed by 2-APB. In addition, a novel role of 2-APB was found in macrophages that causes the upregulation of heat shock protein 70 (HSP70) expression associated with ERK activation; upregulated TNF-α production in the case of knockdown HSP70 was inhibited with 2-APB treatment. Furthermore, elevated HSP70 formation unexpectedly did not help the cell survival of O. tsutsugamushi-infected macrophages. In conclusion, the parallelism between downregulated Ca2+ mobilization via SOCE and upregulated HSP70 after treatment with 2-APB against TNF-α production was found to efficiently attenuate an O. tsutsugamushi-induced severe inflammatory response.
Highlights
The immune system defends the body from infectious pathogens in two major ways: innate and adaptive immunity
Our results indicate that 2-aminoethoxydiphenyl borate (2-APB) decreases store-operated Ca2+ entry (SOCE) activity to regulate tumor necrosis factor (TNF)-α production, and upregulates heat shock protein 70 (HSP70) to reduce TNF-α expression via the activation of the mitogen-activated protein kinase (MAPK)/ERK pathway in O. tsutsugamushi-infected macrophages
The present study found a new mechanism of 2-APB for inhibiting inflammation-induced TNF-α production via upregulation of the ERK/HSP70 axis in O. tsutsugamushi-infected macrophages
Summary
The immune system defends the body from infectious pathogens in two major ways: innate and adaptive immunity. It has been established that Ca2+ signaling regulates the production of a variety of cytokines as part of a severe inflammatory response that results from complicated pathogen infections [10]. Clinical studies have led to the development of new therapeutic approaches against severe inflammation and sepsis, the major focus has been on decreasing the cytokine storm, especially tumor necrosis factor (TNF)-α production [11,12,13]. Our results indicate that 2-APB decreases SOCE activity to regulate TNF-α production, and upregulates heat shock protein 70 (HSP70) to reduce TNF-α expression via the activation of the MAPK/ERK pathway in O. tsutsugamushi-infected macrophages. We propose in this report that there is a novel pathway for 2-APB to regulate pathogeninduced TNF-α production in macrophages and that an inhibitory mechanism against pathogen infection by 2-APB mitigates a cytokine storm during a severe inflammatory response
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