Intracellular Signaling Pathways that Regulate Macrophage Chemokine Expression in Response to Mycobacterium abscessus

ABSTRACT

Mycobacterium abscessus (Mabc) is an emerging human pathogen. Less is known about the host immune response to Mabc than to M. tuberculosis. Here, we examined the intracellular signaling pathways that govern the expression of chemokines including (C-C motif) ligand 2 (CCL2) and (C-X-C motif) ligand 2 (CXCL2) in macrophages after infection with Mabc. Specifically, Mabc triggered the generation of reactive oxygen species (ROS) and the production of CCL2 and CXCL2 in murine bone marrow-derived macrophages (BMDMs). Mabc-induced CCL2, but not CXCL2, was dependent on the generation of ROS. Toll-like receptor (TLR) 2, MyD88, but not TRIF, was required for Mabc-induced CCL2 and CXCL2 expression. Additionally, Mabc infection significantly induced nuclear factor (NF)-kappaB nuclear translocation and luciferase activity. The activation of NF-kappaB was required for Mabc-induced CCL2, but not CXCL2 expression. Moreover, Mabc-induced ROS generation was required for NF-kappaB activation. Treatment of BMDMs with Mabc rapidly induced the activation of mitogen-activated protein kinase (MAPKs) pathways. Interestingly, CCL2 expression was dependent on the activation of JNK and ERK1/2 pathways, whereas it was negatively regulated by the p38 MAPK pathway. In contrast, Mabc-dependent CXCL2 expression was not regulated by MAPK pathways. These data suggest that intracellular ROS generation is required for innate and inflammatory responses during Mabc infection of macrophages.