Mycobacterium tuberculosis in a Trap: The Role of Neutrophil Extracellular Traps in Tuberculosis

Abstract

Mycobacterium tuberculosis complex causes tuberculosis (TB), a disease that causes pulmonary inflammation but can also affect other tissues. Despite macrophages having a defined role in TB immunopathogenesis, other innate immune cells, such as neutrophils, are involved in this process. These cells have high phagocytic ability and a microbial-killing machine comprised of enzymes, antimicrobial peptides, and reactive oxygen species. In the last two decades, a new neutrophil immune response, the neutrophil extracellular traps (NETs), has been intensely researched. NETs comprise DNA associated with histones, enzymes, and antimicrobial peptides. These structures are related to antimicrobial immune response and some immuno-pathogenesis mechanisms. This mini review highlights the role of NETs in tuberculosis and how they can be helpful as a diagnostic tool and/or therapeutic target.

Keywords: NETs; innate immunity; mycobacteria.

Figure 1

Mycobacterium tuberculosis (Mtb) infection begins with the recognition and internalization of bacteria by alveolar macrophages, allowing replication and establishment of infection. The immune response involves the secretion of cytokines and chemokines, recruitment of phagocytes, and activation of adaptive immunity, particularly CD4⁺ and CD8⁺ T cells. Monocytes and neutrophils are recruited to the infection site, potentially aiding bacterial dissemination. Dendritic cells play a crucial role in priming adaptive immune responses, presenting Mtb antigens to T cells in lymph nodes. In the lungs and other tissues, granulomas can form. They are a complex immune response mechanism aimed at containing and neutralizing pathogens, and their formation plays a significant role in the pathology of tuberculosis. Dissemination of Mtb from the lungs to extrapulmonary sites can occur through hematogenous spread or direct extension from adjacent lymph nodes or tissues. The immune response in extrapulmonary TB may exhibit variations depending on the involved tissue. Created with Biorender.com (accessed on 7 July 2023).

Figure 2

Mycobacterium tuberculosis (Mtb) and its antigens (e.g., ESAT-6 and Rv0888) induce neutrophil extracellular trap release (NETs). This mechanism can capture but not kill Mtb. The underlying mechanisms responsible for Mtb-induced release of neutrophil extracellular traps (NETs) involve the elevation of reactive oxygen species (ROS) levels and an increase in intracellular calcium ions (Ca²⁺). Experimental evidence has demonstrated that under other stimuli, ROS facilitates the activation of myeloperoxidase (MPO) and neutrophil elastase (NE), promoting their translocation from neutrophil granules to the nucleus, thereby triggering the subsequent release of NETs. Moreover, Ca²⁺ serves as a crucial signaling molecule, capable of activating numerous proteins, including peptidylarginine deiminase 4 (PAD4), an enzyme that plays a pivotal role in inducing histone citrullination—a critical step in the process of NET formation. Some resistance mechanisms may be associated (e.g., perhaps DNase release). The NETs can induce macrophages to release cytokines (e.g., IL-6, IL-1β, and TNF-α) that favor neutrophil influx. Macrophages can also internalize NETs; in macrophage lysosomes, NETs peptides could kill M. tuberculosis. Created with Biorender.com (accessed on 7 July 2023).