title: Caspase-independent apoptosis in infected macrophages triggered by sulforaphane via Nrf2/p38 signaling pathways.
abstract: Mycobacterium abscessus (Mabs), a non-tuberculous mycobacterium, is an emerging and rapidly growing opportunistic pathogen that is frequently found in patients with cystic fibrosis and in immunosuppressed patients. Its high tolerance to antibiotics is of great concern for public health. In this study, our results showed that human THP-1-derived macrophages infected with M. abscessus presented an increase in ROS production and cell necrosis. In addition, M. abscessus infection triggered activation of the Nuclear factor E2-related factor 2 (Nrf2) signaling pathway, and the induction of HO-1 and NQO1 expression levels. Interestingly, pretreatment of macrophages with sulforaphane (SFN), an activator of the antioxidant key regulator Nrf2, followed by M. abscessus infection significantly decreased mycobacterial burden. We demonstrated that this reduction in mycobacterial growth was due to an activation in cell apoptosis in SFN-pretreated and M. abscessus-infected macrophages. Pretreatment with specific MAPK inhibitors, PD98059, SP600125, and SB203580 to ERK, JNK, and p38 respectively, failed to inhibit induction of Nrf2 expression, suggesting that Nrf2 signaling pathway was upstream of MAPK signaling. Activation of cell apoptosis was caspase 3/7 independent but p38 MAPK dependent. Moreover, p38 MAPK induction was abolished in macrophages transfected with Nrf2 siRNA. In addition, p38 inhibitor abolished Nrf2-dependent apoptosis in infected macrophages. Taken together, our results indicate that modulation of the Nrf2 signaling using Nrf2 activators may help potentiate the actual drug therapies used to treat mycobacterial infection.
authors.affiliation: Laboratoire de Physiologie TITAN, INSERM U1179, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France; Service de Physiologie-Explorations Fonctionnelles, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne, France; LIA-BAHN (Laboratoire International Associé-Biologie Appliquée Handicap Neuromusculaire), CSM (Centre Scientifique de Monaco), Monaco.
authors.forename: M
authors.identifier: 0000-0003-1446-7456
authors.initials: M
authors.lastname: Bonay
authors.affiliation: INSERM U1173, Equipe EPIM, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines , Montigny-le-Bretonneux, France.
authors.forename: A-L
authors.initials: AL
authors.lastname: Roux
authors.affiliation: Laboratoire de Physiologie TITAN, INSERM U1179, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines , Montigny-le-Bretonneux, France.
authors.forename: J
authors.initials: J
authors.lastname: Floquet
authors.affiliation: Laboratoire de Physiologie TITAN, INSERM U1179, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France; Service de Physiologie-Explorations Fonctionnelles, Hôpital Ambroise Paré, Assistance Publique-Hôpitaux de Paris, Boulogne, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Retory
authors.affiliation: INSERM U1173, Equipe EPIM, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines , Montigny-le-Bretonneux, France.
authors.forename: J-L
authors.initials: JL
authors.lastname: Herrmann
authors.affiliation: Laboratoire de Physiologie TITAN, INSERM U1179, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines , Montigny-le-Bretonneux, France.
authors.forename: F
authors.initials: F
authors.lastname: Lofaso
authors.affiliation: Laboratoire de Physiologie TITAN, INSERM U1179, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France; LIA-BAHN (Laboratoire International Associé-Biologie Appliquée Handicap Neuromusculaire), CSM (Centre Scientifique de Monaco), Monaco.
authors.forename: T B
authors.initials: TB
authors.lastname: Deramaudt