Mycobacterium tuberculosis-Induced Neutrophil Extracellular Traps Activate Human Macrophages

Abstract

Neutrophils activated by Mycobacterium tuberculosis (Mtb) form neutrophil extracellular traps (NETs), containing DNA and several biologically active cytosolic and granular proteins. These NETs may assist in the innate immune defense against different pathogens. We investigated whether the NET-forming neutrophils mediate an activating signal to macrophages during the early multicellular inflammatory reaction and granuloma formation. Mtb-induced NETs were found to be reactive oxygen species dependent and phagocytosis dependent. A neutrophil elastase inhibitor also delayed NET formation. However, NET formation occurred independently of Mtb-induced apoptosis. We observed close interactions between macrophages and Mtb-activated neutrophils, where macrophages bound and phagocytosed NETs. Significant secretion of the cytokines interleukin (IL)-6, tumor necrosis factor-α, IL-1β and IL-10 were detected from macrophages cocultured with NETs from Mtb-activated but not phorbol myristate acetate-activated neutrophils. NETs binding heat shock protein 72 (Hsp72) or recombinant Hsp72 were able to trigger cytokine release from macrophages. Only Mtb-induced NETs contained Hsp72, suggesting that these NETs can transfer this danger signal to adjacent macrophages. We propose that Hsp72 sequestered in NETs plays an important role in the interaction between neutrophils and macrophages during the early innate immune phase of an Mtb infection. The immunomodulatory role of NETs and proteins derived from them may influence not only chronic inflammation during tuberculosis but also immune regulation and autoimmunity.

Mycobacterium tuberculosis and the human macrophage : shifting the balance through inflammasome activation

“…After induction of apoptosis, the apoptotic neutrophils are recognized and cleared by other adjacent phagocytes. While studies in our lab have shown that uptake of neutrophils, which are apoptotic as a consequence of phagocytosing mycobacteria, by human macrophages induces a proinflammatory response in the macrophage (387)(388)(389), uptake of spontaneously apoptotic neutrophils have long been implicated in anti-inflammatory responses and resolution of inflammation (390). However, since the site of infection at early stages likely contains both mycobacteria-infected and spontaneously apoptotic neutrophils, a downregulation of macrophage responses by the latter could have detrimental effects for the host.…”

The Neutrophil: A Beautiful Beast or a Beastly Beauty?

“…However, they can also recognize damage-associated molecular patterns (DAMPs) during tissue-damage and participate in viral host defense [12,13] . Another important function is the formation of neutrophil extracellular traps (NETs), formed during an active cellular process where the neutrophil releases its DNA to the extracellular environment [14,15] . Finally, resolution of neutrophil inflammation has to be tightly regulated to avoid accumulation of these cells, as is exemplified by the prolonged and excessive inflammation in cystic fibrosis [16][17][18] .…”

A Farewell to Arms: Streptococcal Strategies to Cope with Innate Immunity

“…Another more recently described way for neutrophils to counteract bacterial dissemination is through the release of nuclear DNA resulting in the formation of NETs [14] . S. pyogenes , like many other bacterial species, can escape entrapment in NETs through the release of extracellular DNase [15,16] .…”