TNF in Human Tuberculosis: A Double-Edged Sword

Abstract

TNF, a pleiotropic proinflammatory cytokine, is important for protective immunity and immunopathology during Mycobacterium tuberculosis (Mtb) infection, which causes tuberculosis (TB) in humans. TNF is produced primarily by phagocytes in the lungs during the early stages of Mtb infection and performs diverse physiological and pathological functions by binding to its receptors in a context-dependent manner. TNF is essential for granuloma formation, chronic infection prevention, and macrophage recruitment to and activation at the site of infection. In animal models, TNF, in cooperation with chemokines, contributes to the initiation, maintenance, and clearance of mycobacteria in granulomas. Although anti-TNF therapy is effective against immune diseases such as rheumatoid arthritis, it carries the risk of reactivating TB. Furthermore, TNF-associated inflammation contributes to cachexia in patients with TB. This review focuses on the multifaceted role of TNF in the pathogenesis and prevention of TB and underscores the importance of investigating the functions of TNF and its receptors in the establishment of protective immunity against and in the pathology of TB. Such investigations will facilitate the development of therapeutic strategies that target TNF signaling, which makes beneficial and detrimental contributions to the pathogenesis of TB.

Keywords: Autophagy; Cell death; Host microbial interactions; Mycobacterium tuberculosis; Pathogenesis; TNF-alpha.

Figure 1. Schematic diagram of the synthesis and receptor signaling pathways of TNF. TNFR1 signaling involves the formation of complexes I and II. Complex I initiates proinflammatory responses and promotes cell survival via the canonical NF-κB and MAPK pathways. In the absence of RIPK1 ubiquitination, complex II formation occurs, leading to caspase-dependent apoptosis or MLKL-dependent necroptosis, depending on caspase-8 activity. TNFR2 signaling begins with the binding of TRAF proteins and promotes cell survival and proliferation via the PI3K/AKT pathway. It also induces non-canonical NF-κB activation mediated by NIK.

PI3K, phosphoinositide 3-kinase; NIK, NF-κB–inducing kinase; ADAM17, a disintegrin and metalloprotease 17; FLIP, FADD–like IL-1β–converting enzyme–like inhibitory protein; IKK, inhibitor of NF-κB kinase; NEMO, NF-κB essential modulator; TAK1, transforming growth factor-β–activated kinase 1; TAB, TGF-β–activated kinase 1–binding protein; AP1, activator protein 1; TF, transcription factor.

Figure 2. Regulatory pathways of TNF-α production in response to Mtb infection. TNF-α induces Mtb-infected macrophage polarization to M1 macrophages, which exert a bactericidal effect by producing iNOS, IFN-γ, T-bet, CCR7, CCL19/21, and IL-1β. M1 macrophages also produce lactate via enhanced aerobic glycolysis, which inhibits bacterial growth. After Mycobacterium bovis BCG vaccination, the production of IFN-γ and TNF-α increases in response to Mtb and Staphylococcus aureus infection, respectively. SQSTM1 agonists activate autophagy and reduce the TNF-α level. By contrast, the Mtb protein PE6 inhibits autophagy and stimulates TNF-α production during Mtb infection. Fluoxetine, an antidepressant, enhances autophagy and increases Mtb-induced TNF-α level. During Mtb infection, IL-1β increases TNFR1 expression and TNF-α secretion, leading to apoptosis to regulate intracellular Mtb growth. However, Mtb induces IL-10 secretion and soluble TNFR2 release, thereby suppressing apoptosis.

T-bet, T-box transcription factor TBX21; CCL19/21, chemokine (C-C motif) ligands 19 and 21.