Innate signaling mechanisms controlling Mycobacterium chelonae-mediated CCL2 and CCL5 expression in macrophages

Abstract

Mycobacterium chelonae (Mch) is an atypical rapidly growing mycobacterium (RGM) that belongs to the M. chelonae complex, which can cause a variety of human infections. During this type of mycobacterial infection, macrophage-derived chemokines play an important role in the mediation of intracellular communication and immune surveillance by which they orchestrate cellular immunity. However, the intracellular signaling pathways involved in the macrophage-induced chemokine production during Mch infections remain unknown. Thus, the present study aimed to determine the molecular mechanisms by which Mch activates the gene expressions of chemokine (C-C motif) ligand 2 (CCL2) and CCL5 in murine bone marrow-derived macrophages (BMDMs) and in vivo mouse model. Toll-like receptor 2 (TLR2)-deficient mice showed increased bacterial burden in spleen and lung and decreased protein expression of CCL2 and CCL5 in serum. Additionally, Mch infection triggered the mRNA and protein expression of CCL2 and CCL5 in BMDMs via TLR2 and myeloid differentiation primary response gene 88 (MyD88) signaling and that it rapidly activated nuclear factor (NF)-κB signaling, which is required for the Mch-induced expressions of CCL2 and CCL5 in BMDMs. Moreover, while the innate receptor Dectin-1 was only partly involved in the Mch-induced expression of the CCL2 and CCL5 chemokines in BMDMs, the generation of intracellular reactive oxygen species (ROS) was an important contributor to these processes. Taken together, the present data indicate that the TLR2, MyD88, and NF-κB pathways, Dectin-1 signaling, and intracellular ROS generation contribute to the Mch-mediated expression of chemokine genes in BMDMs.

A Comparative Analysis of Edwardsiella tarda-Induced Transcriptome Profiles in RAW264.7 Cells Reveals New Insights into the Strategy of Bacterial Immune Evasion

“…NF-κB is a vital immune regulator, which can be activated by RIG-I signaling and activates the transcription of a large array of cytokines and other immune genes, such as NOS2 [62,63,64]. In the present work, we observed that the phosphorylation level of NF-κB p65 was decreased upon live versus dead E. tarda infection, indicating a suppression of NF-κB activity by live E. tarda .…”

The Rise of Non-Tuberculosis Mycobacterial Lung Disease

“…However, the mechanism/s and correlates of protection of these responses during the various stages of this chronic disease are not understood. Other studies in the mouse models or murine cells models of NTM infection have shown the importance of CCL2, CCL5, and TLR signaling via MAPK, MyD88, and NFκβ for disease protection (86)(87)(88). Robust mouse models for M. avium infection exist though currently, it is difficult to initiate infection, maintain infection, and measure immune responses in MABS mouse models (89,90).…”