Apoptotic Neutrophils Augment the Inflammatory Response to Mycobacterium tuberculosis Infection in Human Macrophages

Abstract

Macrophages in the lung are the primary cells being infected by Mycobacterium tuberculosis (Mtb) during the initial manifestation of tuberculosis. Since the adaptive immune response to Mtb is delayed, innate immune cells such as macrophages and neutrophils mount the early immune protection against this intracellular pathogen. Neutrophils are short-lived cells and removal of apoptotic cells by resident macrophages is a key event in the resolution of inflammation and tissue repair. Since anti-inflammatory activity is not compatible with effective immunity to intracellular pathogens, we therefore investigated how uptake of apoptotic neutrophils modulates the function of Mtb-activated human macrophages. We show that Mtb infection exerts a potent proinflammatory activation of human macrophages with enhanced gene activation and release of proinflammatory cytokines and that this response was augmented by apoptotic neutrophils. The enhanced macrophage response is linked to apoptotic neutrophil-driven activation of the NLRP3 inflammasome and subsequent IL-1β signalling. We also demonstrate that apoptotic neutrophils not only modulate the inflammatory response, but also enhance the capacity of infected macrophages to control intracellular growth of virulent Mtb. Taken together, these results suggest a novel role for apoptotic neutrophils in the modulation of the macrophage-dependent inflammatory response contributing to the early control of Mtb infection.

Extracellular traps and macrophages: new roles for the versatile phagocyte

“…In contrast to NETs generated upon PMA treatment, mycobacteria-induced NETs up-regulated the production of IL-6, TNF-a, IL-1b, and IL-10 by MF upon phagocytosis of the ETs. Furthermore, infectioninduced NETs contained Hsp72, which was absent in PMAactivated NETs, a finding in accordance with prior observations that Hsps expressed by infection-induced apoptotic neutrophils can activate MF toward a proinflammatory phenotype [181][182][183][184]. Although Hsp72 alone was capable of stimulating inflammatory cytokine production, the observed response was much greater when Hsp72 was bound in NETs, whether Local signaling mechanisms may attune the behavior of MF to the surrounding environment, enhancing inflammation when the phagocytes encounter the remains of ETs and microbes or initiating MF-mediated resolution of the inflammatory response and subsequent tissue repair postinjury or infection.…”

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…However, increasing evidence suggests a supportive role for PMN in protective immunity. PMN can indirectly augment IL-1β-mediated inflammatory responses in macrophages after contact with Mtb (202, 204, 205). Also, and consistent with Th17 responses, PMN play an essential role in generation of protective recall responses in Mtb-infected mice (195, 206, 222).…”

MyD88 in Mycobacterium tuberculosis infection

“…Lifespan of neutrophils is short, and removal of apoptotic cells by resident macrophages is key in the resolution of inflammation. Dying neutrophils also enhance the capacity of infected macrophages to control intracellular growth of Mtb [69]. NLRP3 inflammasome activation and IL-1β signaling by neutrophils, however, appear to enhance macrophage proinflammatory activation.…”