Abstract
Despite the extensive research on Notch signaling involvement in inflammation, its specific role in macrophage response in autoimmune disease and defense mechanisms against bacterial infection, such as Mycobacterium avium paratuberculosis (MAP), remains unknown. In this study, we investigated the molecular role of Notch-1 signaling in the macrophage response during MAP infection. In particular, we measured the in vitro effect of MAP on Notch-1 signaling and downstream influence on interleukin (IL)-6 and myeloid cell leukemia sequence-1 (MCL-1) and consequent cellular apoptosis, MAP viability, and macrophage polarization. Overall, the data show significant upregulation in Notch-1, IL-6, and MCL-1 in MAP-infected macrophages, parallel with a decrease in apoptosis and elevated pro-inflammatory response in these infected cells. On the contrary, blocking Notch signaling with γ-secretase inhibitor (DAPT) decreased MAP survival and burden, increased apoptosis, and diminished the pro-inflammatory response. In particular, the treatment of infected macrophages with DAPT shifted macrophage polarization toward M2 anti-inflammatory phenotypic response. The outcome of this study clearly demonstrates the critical role of Notch signaling in macrophage response during infection. We conclude that MAP infection in macrophages activates Notch-1 signaling and downstream influence on IL-6 which hijack MCL-1 dependent inhibition of apoptosis leading to its chronic persistence, and further inflammation. This study supports Notch-1 signaling as a therapeutic target to combat infection in autoimmune diseases such as Crohn’s disease and Rheumatoid Arthritis.
Highlights
Notch signaling is an evolutionary-conserved pathway that mediates juxtracrine cell communication through the receptor–ligand interaction
The activation of the Notch receptor by the transmembrane ligand on juxtaposed cells leads to proteolytic cleavage of the Notch receptor by the γ-secretase complex, which eventually leads to the release and nuclear translocation of the Notch intracellular domain (NICD), where it interacts with DNA binding protein CSL (C promotor-binding factor 1 (CBF1)/RBP-J in humans, suppressor of hairless in Drosophila melanogaster, Lin-12 and Glp-1 (Lag-1) in Caenorhabditis elegans), and activates the transcription of Notch target genes such as hairy enhancer of split (HES) and HES with YRPW motif (HEY) [1]
To explore the effect of Mycobacterium avium paratuberculosis (MAP) infection on Notch-1, IL-6, and myeloid cell leukemia sequence-1 (MCL-1) expression in infected macrophages, THP-1-derived macrophages were infected with MAP (107 colony-forming units per milliliter (CFU/mL)) for 24 h
Summary
Notch signaling is an evolutionary-conserved pathway that mediates juxtracrine cell communication through the receptor–ligand interaction. A considerable body of literature has confirmed the role of Notch signaling in immune cell development and function [1,2]. The role of Notch signaling in lymphocyte development and functions is well accepted, there is still considerable ambiguity about the role of Notch signaling in myeloid cells including macrophages [3]. This includes the role of Notch signaling in the macrophage immune response, and defense mechanisms against intracellular bacterial infections which remain unknown
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