Autophagy in the immune response to tuberculosis: clinical perspectives

Abstract

A growing body of evidence points to autophagy as an essential component in the immune response to tuberculosis. Autophagy is a direct mechanism of killing intracellular Mycobacterium tuberculosis and also acts as a modulator of proinflammatory cytokine secretion. In addition, autophagy plays a key role in antigen processing and presentation. Autophagy is modulated by cytokines; it is stimulated by T helper type 1 (Th1) cytokines such as tumour necrosis factor (TNF)-α and interferon (IFN)-γ, and is inhibited by the Th2 cytokines interleukin (IL)-4 and IL-13 and the anti-inflammatory cytokine IL-10. Vitamin D, via cathelicidin, can also induce autophagy, as can Toll-like receptor (TLR)-mediated signals. Autophagy-promoting agents, administered either locally to the lungs or systemically, could have a clinical application as adjunctive treatment of drug-resistant and drug-sensitive tuberculosis. Moreover, vaccines which effectively induce autophagy could be more successful in preventing acquisition or reactivation of latent tuberculosis.

Fig. 1

Modulation of autophagy in macrophages. Autophagy can be induced by mammalian target of rapamycin (mTOR) inhibitors, such as rapamycin, by drugs acting via the D-myo-inositol-1,4,5-trisphosphate (IP3) pathway, such as sodium valproate, by vitamin D (through the induction of the anti-microbial peptide cathelicidin) and by cytokines, including tumour necrosis factor (TNF)-α and interferon (IFN)-γ. Induction of autophagy by IFN-γ is dependent on immunity-related GTPase M (Irgm1/IRGM) and may act, at least partially, through the induction of TNF-α in cells infected with mycobacteria. Other cytokines, including interleukin (IL)-4, IL-13 and IL-10 inhibit autophagy through protein kinase B (Akt), signal transducer and activator of transcription (STAT)6 and STAT3 signalling pathways. In cells infected with Mycobacterium tuberculosis, induction of autophagy leads to increased acidification and maturation of mycobacteria-containing phagosomes and increased killing of intracellular bacteria. Autophagy also plays a role in antigen presentation and inhibits the processing and secretion of proinflammatory cytokines, including IL-1β and IL-18.

Fig. 2

Interleukin (IL)-10 inhibits lipopolysaccharide (LPS)-induced autophagy in macrophages. Immortalized murine bone marrow-derived macrophages stably transfected with green fluorescent protein-(GFP)-LC3 were treated with LPS (100 ng/ml) in the presence or absence of recombinant murine IL-10 (10 ng/ml) for 24 h. Autophagy induction was determined by counting the number of GFP-LC3⁺ vesicles per cell. Data are means ± standard error of the mean from three separate experiments. Data were analysed using a one-way analysis of variance, followed by Tukey's honestly least significance post-test. Scale bar = 10 µm.