The role of reactive oxygen species in macrophage-mediated immune response against Mycobacterium tuberculosis

Mycobacterium tuberculosis (Mtb) is the primary pathogen that causes tuberculosis in humans. As the primary target cells, macrophages employ reactive oxygen species (ROS) as a crucial defense against Mtb. However, the dynamic and reciprocal interplay between Mtb, macrophages, and ROS-where each component actively influences the others-forms a complex network that remains underexplored. This review aims to synthesize recent advances and proposes a novel conceptual framework centered on this tripartite interaction. Cytoplasmic NADPH oxidase (NOX) and mitochondria in macrophages act as major sources of ROS. Their production could activate multiple signaling pathways, including NF-κB, the MAPK family, and Nrf2. The increasing ROS levels play crucial roles in maintaining the activation of macrophages and their M1 polarization through driving metabolic reprogramming. ROS also play a vital role in activating the autophagy and apoptosis pathways in macrophages. To maintain the long-term survival, Mtb could evade the immune system by manipulating host oxidative stress pathways, as well as the death patterns of infected macrophages. It employs the antioxidant enzymes, such as KatG, to resist ROS-mediated killing. Virulent Mtb strains suppress apoptosis in macrophages, enabling the survival and replication within host cells. By elucidating this multifaceted interplay, our review highlights new insights into tuberculosis pathogenesis and suggests that future therapeutic strategies could involve precisely modulating this tripartite network to reactivate anti-Mtb immunity. However, significant challenges remain, as clinical trials on antioxidants in the TB field are still limited, and strategies for therapeutically applying ROS in anti-TB treatment are largely exploratory.