Abstract
Mycobacterium tuberculosis (MTB) infection induces cytotoxicity to host human macrophages. The underlying signaling mechanisms are largely unknown. Here we discovered that MTB infection induced programmed necrosis in human macrophages, causing mitochondrial cyclophilin-D (CypD)-p53-adenine nucleotide translocator type 1 association, mitochondrial depolarization and lactate dehydrogenase medium release. In human macrophages MTB infection-induced programmed necrosis and apoptosis were largely attenuated by CypD inhibition (by cyclosporin A), silencing and knockout, but intensified with ectopic CypD overexpression. Further studies identified microRNA-1281 as a CypD-targeting miRNA. Ectopic overexpression of microRNA-1281 decreased CypD 3’-untranslated region activity and its expression, protecting human macrophages from MTB-induced programmed necrosis and apoptosis. Conversely, microRNA-1281 inhibition in human macrophages, by the anti-sense sequence, increased CypD expression and potentiated MTB-induced cytotoxicity. Importantly, in CypD-KO macrophages miR-1281 overexpression or inhibition was ineffective against MTB infection. Restoring CypD expression, by an untranslated region-depleted CypD construct, reversed miR-1281-induced cytoprotection against MTB in human macrophages. Collectively, these results show that targeting CypD by miR-1281 protects human macrophages from MTB-induced programmed necrosis and apoptosis.
Highlights
Macrophages, among other host immune cells, are essential in determining immune responses against Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) [1], which causes an estimated over 1.5 million human mortalities each year [2]
These results suggested that MTB infection induced mitochondria permeability transition pore (mPTP) opening and programmed necrosis in human macrophages
In the present study we show that MTB infection led to programmed necrosis in human macrophages, causing CypD-p53-adenine nucleotide translocator type 1 (ANT1) mitochondrial association, mitochondrial depolarization and lactate dehydrogenase (LDH) release
Summary
Macrophages, among other host immune cells, are essential in determining immune responses against Mycobacterium tuberculosis (MTB) infection and tuberculosis (TB) [1], which causes an estimated over 1.5 million human mortalities each year [2]. Studies have shown that MTB spread will be facilitated with the death of the infected macrophages [1, 3, 4], caused often by the extracellular growth of released MTB or less cleared MTB in dead macrophages [3, 5]. Recent literatures have indicated that cell necrosis could be a programmed, mitochondriadependent and active cell death [7,8,9,10]. This so-called “programmed necrosis” can promote cell death by a number of different stresses and stimuli, including oxidative injury, calcium over-load and several chemoagents [7, 8, 11, 12]. In the progression of programmed necrosis, p53 translocates to cell mitochondria to form a complex with mitochondria permeability transition pore (mPTP) components, including cyclophilin-D (CypD) and adenine nucleotide translocator type 1 (ANT1) [13, 14]
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