Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins

Abstract

Modulation of immune cell apoptosis is a key evasion strategy utilized by Mycobacterium tuberculosis (Mtb). To be able to multiply within macrophages, the bacterium delays apoptosis and down-regulates pro-inflammatory activation in these cells, whereas apoptosis is rapidly induced in the potently bactericidal neutrophils. Initial host-pathogen interactions between neutrophils and Mtb, subsequently leading to apoptosis, need to be investigated to understand the early features during Mtb infections. Opsonized Mtb were readily phagocytosed, and the immuno-mediated phagocytosis triggered early activation of anti-apoptotic Akt in the neutrophils but the bacteria still induced apoptosis to the same extent as non-phagocytosed Mtb. Mtb-induced apoptosis was strictly dependent on NADPH oxidase-generated reactive oxygen species, compounds shown to damage lysosomal granules. Despite this, we found no involvement of damaged azurophilic granules in Mtb-induced apoptosis in human neutrophils. Instead, the Mtb-induced apoptosis was p38 MAPK dependent and induced through the mitochondrial pathway. Moreover, Mtb deficient of mature lipoproteins lacked the determinants required for induction of neutrophil apoptosis. These results show that Mtb exert a strong intrinsic capacity to induce apoptosis in neutrophils that is capable of overcoming the anti-apoptotic signaling in the cell.Original Publication:Alexander Persson, Robert Blomgran, Daniel Eklund, Charlotte Lundstrom and Olle Stendahl, Induction of apoptosis in human neutrophils by Mycobacterium tuberculosis is dependent on mature bacterial lipoproteins, 2009, MICROBIAL PATHOGENESIS, (47), 3, 143-150.http://dx.doi.org/10.1016/j.micpath.2009.05.006Copyright: Elsevier Science B.V., Amsterdamhttp://www.elsevier.com

Mycobacterium tuberculosis-Induced Neutrophil Extracellular Traps Activate Human Macrophages

“…Persson et al [21] also showed that an Mtb lspA-/- mutant lacking the 19-kDa lipoprotein did not induce apoptosis in neutrophils. Using this Mtb mutant, we investigated whether apoptosis was a prerequisite for Mtb-induced NET formation.…”

“…Considering our previous observations that Mtb-induced apoptotic neutrophils can induce a proinflammatory activation of macrophages [18,19,20,21], we asked whether NETs could mediate this activating signal to macrophages. Macrophages and neutrophils coexist at the inflammation site and work in concert to remove pathogens [29].…”

“…In another context, neutrophil-derived elastase from apoptotic neutrophils was able to activate macrophages via modulation of Toll-like receptor 4 (TLR4) and an increase in tumor necrosis factor (TNF)-α that led to increased killing of Leishmania major [17]. We have earlier shown that Mtb infection increases the rate of neutrophil apoptosis and that pathogen-induced apoptotic neutrophils trigger a proinflammatory response in macrophages [18,19,20], which was mediated by the release of heat shock protein 72 (Hsp72) [20,21]. …”

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

“…However, unlike macrophages, neutrophils are prone to undergo apoptosis upon infection with wild type M. tuberculosis expressing the 19 kDa lipoprotein (232)(233). Subsequent uptake of apoptotic neutrophils or macrophages by other phagocytes, primarily macrophages, plays a role in infections and helps modulate the immune response.…”

“…Uptake of mycobacteria by neutrophils leads to killing of the bacteria as well as induction of apoptosis. However, non-infected neutrophils at the site of infection are still shortlived cells and undergo apoptosis spontaneously within 24 hours after leaving circulation (231)(232). After induction of apoptosis, the apoptotic neutrophils are recognized and cleared by other adjacent phagocytes.…”