Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation

Abstract

Autophagy is a cell biological pathway affecting immune responses. In vitro, autophagy acts as a cell-autonomous defense against Mycobacterium tuberculosis, but its role in vivo is unknown. Here we show that autophagy plays a dual role against tuberculosis: antibacterial and anti-inflammatory. M. tuberculosis infection of Atg5 fl/fl LysM-Cre + mice relative to autophagy-proficient littermates resulted in increased bacillary burden and excessive pulmonary inflammation characterized by neutrophil infiltration and IL-17 response with increased IL-1α levels. Macrophages from uninfected Atg5 fl/fl LysM-Cre + mice displayed a cell-autonomous IL-1α hypersecretion phenotype, whereas T cells showed propensity toward IL-17 polarization during nonspecific activation or upon restimulation with mycobacterial antigens. Thus, autophagy acts in vivo by suppressing both M. tuberculosis growth and damaging inflammation.utophagy is a fundamental cell biological process (1) with impact on aging, development, cancer, neurodegeneration, myodegeneration, metabolic disorders (2), idiopathic inflammatory diseases, and infection and immunity (3). Much of the physiological effects of autophagy are the result of degradative activities of autophagy (1), although biogenesis and secretory roles (4-6) of autophagy are beginning to be recognized (7). The execution of autophagy depends on factors collectively termed "Atg proteins," such as Atg5 (1) and Beclin 1 (Atg6) (8), whereas regulation of autophagy responds to various inputs via mammalian target of rapamycin (mTOR), including the presence of microbes (9), the TAB2/3-TAK1-IKK signaling axis (10), and processes downstream of pattern-recognition receptors and immune cytokine activation (3,(11)(12)(13).In the context of its immunological functions, autophagy acts in four principal ways (14). (i) Autophagy cooperates with conventional pattern-recognition receptors (PRRs), such as Toll-like receptors, RIG-I-like receptors (RLRs), and NOD-like receptors, and acts as both a regulator (11,12,15,16) and an effector of PRR signaling (17-19). (ii) Autophagy affects the presentation of cytosolic antigens in the context of MHC II molecules (20) in T-cell development, differentiation, polarization, and homeostasis (21,22). (iii) Most recently, autophagy has been shown to contribute to both the negative (6,7,(23)(24)(25) and positive (6, 7) regulation of unconventional secretion of the leaderless cytosolic proteins known as "alarmins," such as IL-1β and HMGB1. (iv) Autophagy can capture and eliminate intracellular microbes, including Mycobacterium tuberculosis (17, 26-29), which was one of the first two bacterial species (26, 30) to be recognized as targets for autophagic removal. This activity recently has been shown to depend on the recognition and capture of microbes by adaptors that represent a specialized subset of PRRs termed "sequestosome-like receptors" (SLRs) (31).M. tuberculosis is one of the first microbes recognized as being subject to elimination by immunological autophagy by murine and human...

CASP4/caspase-11 promotes autophagosome formation in response to bacterial infection

“…Nevertheless, WT macrophages successfully restrict B. cenocepacia growth, as functional autophagy machinery is restored in WT but not in CF cells [5,41]. Reduced autophagy activity has been implicated in dysfunctional cellular immunity to intracellular pathogens including the bacteria L. pneumophila, M. tuberculosis, L. monocytogenes , and parasites including Toxoplasma gondii [7,42,43]. …”

Role of autophagy in the pathogenesis of multiple sclerosis

“…tuberculosis increases the expression of IL-17, a potent mediator in autoimmunity [33] . In primary effective T-cells, p62 serves as a receptor for autophagic degradation of ubiquitinated BCL10 during TCR activation to protect cells from excessively activated NF-κB pathway [34] .…”

“…Blockade of autophagy leads to the activation of inflammasomes which control the proteolytic processing and secretion of IL -1β and IL-18 under infl ammatory stress [30,31] . Also, ablation of autophagyrelated 16-like 1 (ATG16L1) increases the production of Peizhou Liang, et al Role of autophagy in the pathogenesis of multiple sclerosis 437 IL-1β and IL-18 in the mouse model of Crohn's disease [32] .Moreover, infection of ATG5-defi cient myeloid cells with M.tuberculosis increases the expression of IL-17, a potent mediator in autoimmunity [33] . In primary effective T-cells, p62 serves as a receptor for autophagic degradation of ubiquitinated BCL10 during TCR activation to protect cells from excessively activated NF-κB pathway [34] .…”

Loss of autophagy enhances MIF/macrophage migration inhibitory factor release by macrophages

“…19 Similarly, mice with deletion of the autophagy gene Atg5 in myeloid cells produce more IL1A and IL17 in response to infection with Mycobacterium tuberculosis. 20 Conversely, induction of autophagy suppresses the secretion of IL1B and IL23, both in vitro and in vivo. 15,19 Together, these findings indicate that autophagy is a process that can directly influence multiple cytokines.…”