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. 2023 Jul 10;14:983299. doi: 10.3389/fmicb.2023.983299

FIGURE 2.

FIGURE 2

M.tb induces formation of NETs in a NADPH-oxidase dependent manner. Infection with M.tb promotes release of NETs. However, NETs trap but do not kill the mycobacterium. (I.1) NET formation begins with phagocytosis of M.tb by neutrophils leading to neutrophil activation in a Ca2+ dependent manner, with ESAT-6 being directly involved. (I.2) The process possibly continues with the activation of a cascade of intracellular enzymes such as protein kinase C and the Raf-MEK-ERK pathway, leading to the phosphorylation of the (I.3) NADPH-oxidase (NOX) which converts O2 to superoxide (O2–) and subsequent generation of ROS. (I.4) (a) A downstream product of NADPH oxidase activation, H2O2, acts as substrate for MPO, and ROS promotes translocation of both NE and MPO from granules to the nucleus where (b) NE mediates chromatin degradation and decondensation by binding to histones. (I.5) PAD4 would also contribute to decondensation of the chromatin by histone citrullination in a process that is dependent on Ca2+. (II) DNA extrusion and chromatin decondensation contributes to nuclear swelling and to the disruption of the nuclear membrane. Therefore, chromatin fills the cell and would be released as a NET upon cell lysis, a process in which pore-forming proteins such as GSDMD, which is activated by NE, also participate. (III) NETs are finally released into the extracellular space containing different granular proteins and histones associated to tissue damage, as well as bacteria and bacterial components such as ESAT-6 that would co-localize with MPO. On the other hand, NETs sequester the toxic contents from dying neutrophils preventing damage to surrounding tissue. Created with BioRender.com. M.tb, Mycobacterium tuberculosis; NADPH-oxidase, nicotinamide adenine dinucleotide phosphate oxidase; ROS, reactive oxygen species; NETs, neutrophil extracellular traps; ESAT-6, early secretory antigenic target 6; NE, neutrophil elastase; MPO, myeloperoxidase; PKC, protein kinase C; PAD4, peptidylarginine deiminase 4; GSDMD, gasdermin D.