Tuberculosis (TB) is the world’s major infectious disease killer, accounting for 1.4 million deaths in 2015 (1). Progress in developing vaccines, diagnostics, and therapies has been hampered by an incomplete understanding of the immune response to the causative pathogen, Mycobacterium tuberculosis (Mtb).

Following entry of Mtb-containing droplets into the airways, bacilli are initially phagocytosed by alveolar macrophages (AMφ), providing a comfortable niche in which Mtb can reside, replicate, and evade immune cell detection (2). Mycobacterial pathogen-associated molecular patterns engage pattern recognition receptors (PRRs) to trigger signaling pathways, resulting in the release of various chemokines and cytokines and the recruitment and activation of immune cells (3). This process results in the internalization of mycobacteria by dendritic cells (DCs), which migrate to lymph nodes where they polarize naïve T cells to antigen-specific Th1 effector cells in an IL-12-dependent manner (4, 5). IFN-γ produced by Th1-polarized T cells activates mycobactericidal mechanisms in AMφ (6). Various immune cells are sequentially recruited to the sites of infection; neutrophils in the earliest stages as well as T cells, NK cells, and fibroblasts. These surround the infected AMφ to form a mycobacterial granuloma (2, 7), which acts as a “physical barrier” limiting bacillary dissemination. However, chronic granulomas also promote Mtb’s intracellular survival and impair elimination, resulting clinically, in latent TB disease (2). One-third of the world’s population is latently infected with Mtb and between 1 and 10% will develop progressive TB disease following “reactivation” of infection in later life (8). The mechanism of TB reactivation is unclear as yet, however, it is suggested that a failure of granuloma maintenance may be the cause (9). Thus, the granuloma is the result of a non-efficient immune control that will eventually progress to a chronic infection, rather than mycobacterial clearance.

Mast cells (MCs) are tissue resident cells strategically located in mucosal tissues (10) and are among the first cells to come in contact with pathogens (11). MCs contribute to bacterial immunity through multiple mechanisms such as bacterial recognition, activation, recruitment of immune cells to the site of infection, release of inflammatory mediators, and direct bacterial killing by extracellular traps (ETs). However, their main role may be orchestrating other immune cells against infections (11–14).

Since little is known about the MC contribution to TB pathogenesis, this review summarizes the MC strategies used in bacterial defense as well as potential and reported interactions occurring between Mtb and MCs (Figure 1).

Mast cells originate from pluripotent CD34⁺ and CD117⁺ hematopoietic stem cells and migrate as progenitors to various tissues where they mature influenced by the local microenvironment (15, 16). MCs are mainly located in the skin (~12,000/mm³) and mucosa including the lungs (~500–4,000/mm³) (10).

Mast cells express various PRRs (e.g., TLRs and CD48), complement receptors, and Fc receptors which upon engagement induce cell activation, degranulation, or both (17). Thereby, MCs release a great variety of pro- and anti-inflammatory pre-stored and de novo synthesized mediators such as histamine, heparin, tryptase, chymase, PGD₂, LTC₄/D₄, chemokines as CCL1, CCL2, CCL4, CCL7, CCL12, CCL17, CXCL5, and CXCL8, and cytokines including IL-4, IL-3, IL-5, GM-CSF, IL-6, IL-13, IL-12, IFN-γ, TGFβ1, and TNF-α (18). This wide variety of products and their rapid release (in min/s) make MCs important modulators of inflammatory responses.

Although interactions between MCs and Mtb have been reported (Figure 1), the role of MCs in TB pathogenesis remains unclear. MC involvement in mycobacterial immunity was first observed in guinea pigs using electron microscopy. Shortly, after intratracheal infection with Mtb, a significant increase in MCs was detected in guinea pig lungs (19). A later study demonstrated that the number of MCs in mice lungs increases by ~23% after 15 days of Mtb exposure (20).

The formation of ETs, named ETosis, is a type of cell death characterized by release of DNA (46). ETosis differs from apoptosis and necrosis since it lacks DNA fragmentation, disruption of the nuclear envelope, absence of phosphatidylserine in the outer membrane and caspase-independent activation (47). The formation of MCETs upon cell stimulation relies on ROS production by MCs that in turn promotes nuclear envelope disruption and release of DNA together with granular components with antimicrobial properties. The DNA backbone in combination with histones, proteases, and AMPs (39, 48) forms physical traps that catch and expose pathogens to high concentrations of antimicrobial molecules (Figure 1B) (48, 49).

A human mast cell line (HMC-1), showed ET formation upon L. monocytogenes infection. This Gram-positive bacterium was shown to promote disruption of the nuclear envelope followed by an increase in ROS production. Interestingly, the presence of β-hexosaminidase in the traps was observed to have an antimicrobial activity to intracellular L. monocytogenes (39). E. faecalis was also found to induce MCET after 3 h of incubation with BMMCs. However, the level of MCET observed was lower compared with the one promoted by other bacteria (43). This was possibly due to the low multiplicity of infection (MOI) used in this study (MOI 1:1). Streptococcus pyogenes induced MCET after infection (MOI 25:1) in HMC-1 cells exhibiting cathelicidin LL-37, histones, and tryptase in the traps and in murine BMMCs displaying tryptase and histones (50). This suggests that high bacterial burden promotes MCET activation. Interestingly, besides bacterial stimulation, IL-12 and IL-1β were found to induce MCET containing IL-17 after the stimulation of MCs from skin explants of patients with psoriasis (51).

Studies involving a broad array of bacterial pathogens have demonstrated the important role of MCs in promoting recruitment, maturation, and bactericidal activity of Mφ, DCs, and neutrophils (Table 1). However, the potential roles of MCs in modulating the delicate orchestration of immune crosstalk in mycobacterial immunity have not yet been described (Figure 1C). MCs could easily coordinate granuloma formation and maintenance. In support of this notion, Taweevisit and Poumsuk reported a correlation between MC numbers and granuloma formation (57). Briefly, 45 lymph nodes from patients with TB lymphadenitis were analyzed to determine the frequency of MCs in the granulomatous region. The authors observed that the number of MCs positively correlated with the number of granulomas. A similar correlation was found between multinucleated giant cells and MCs in the lymph nodes (57). Similar studies have been performed using skin biopsies of patients suffering with leprosy (Mycobacterium leprae) (58). Lepromatous leprosy (disseminated disease with high bacillary load) was associated with the lowest dermal MC density compared with paucibacillary and localized tuberculous leprosy. This suggests that MC functions may have a role in driving a differential susceptibility to these polar forms of leprosy, an as yet poorly explained clinical phenomenon (59). Furthermore, the higher MC numbers located around granulomas in the tuberculous group were considered to be indirect evidence of the role of MCs in activating the immune response to M. leprae infection. Interestingly, numerous MCs were found in the highly fibrotic dermal area and in the epineurial layer of lepromatous leprosy lesions, suggesting that MCs could be involved in the induction of fibrosis, including fibrotic leprosy neuritis (60).

Tuberculosis is a highly contagious infectious disease caused by Mtb which infects billions, and kills millions of people worldwide. Although many efforts have been made to reduce TB mortality, the infection remains one the most important threats to human health. MCs are key lung resident immune sentinels that contribute to antibacterial immunity and are likely to play a key role in TB pathogenesis. A potential important and unique function of MCs is the crosstalk with other immune cells to orchestrate multiple effector functions, which may contribute to granuloma formation and maintenance. We have highlighted the potential roles MCs may play during TB that once addressed could inform the design of novel therapeutic strategies.

KG-R and SB-P conceived, wrote, designed, and coordinated the manuscript. AG, MA-R, and RH-P provided helpful discussions and edited the manuscript. All the authors read and approved the final manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.