GM-CSF Dependent Differential Control of Mycobacterium tuberculosis Infection in Human and Mouse Macrophages: Is Macrophage Source of GM-CSF Critical to Tuberculosis Immunity?

Abstract

Although classically associated with myelopoiesis, granulocyte-macrophage colony-stimulating factor (GM-CSF) is being increasingly recognized for its potential role in innate resistance against tuberculosis (TB). While the GM-CSF is produced by a variety of host cells, including conventional and non-conventional T cells, macrophages, alveolar epithelial cells, the cell population that promotes GM-CSF mediated innate protection against Mycobacterium tuberculosis infection remains unclear. This is because studies related to the role of GM-CSF so far have been carried out in murine models of experimental TB, which is inherently susceptible to TB as compared to humans, who exhibit a resolution of infection in majority of cases. We found a significantly higher amount of GM-CSF production by human macrophages, compared to mouse macrophages, after infection with M. tuberculosis in vitro. The higher levels of GM-CSF produced by human macrophages were also directly correlated with their increased life span and ability to control M. tuberculosis infection. Other evidence from recent studies also support that M. tuberculosis infected human macrophages display heterogeneity in their antibacterial capacity, and cells with increased expression of genes involved in GM-CSF signaling pathway can control intracellular M. tuberculosis growth more efficiently. Collectively, these emerging evidence indicate that GM-CSF produced by lung resident macrophages could be vital for the host resistance against M. tuberculosis infection in humans. Identification of GM-CSF dependent key cellular pathways/processes that mediate intracellular host defense can lay the groundwork for the development of novel host directed therapies against TB as well as other intracellular infections.

BCG‐induced protection against Mycobacterium tuberculosis infection: Evidence, mechanisms, and implications for next‐generation vaccines

“…Additionally, the addition of GM‐CSF made these macrophages more restrictive of Mtb growth, while blockage of GM‐CSF made them more permissive. Further, GM‐CSF production by macrophages is associated with their ability to control intracellular Mtb infection 166 . If GM‐CSF is involved in BCG‐induced training of myeloid precursors, this may generate differentiated macrophages with enhanced anti‐mycobacterial activity and contribute to early clearance of Mtb infection.…”

“…Further, intravesical BCG in combination with recombinant Th1 cytokines such as IFN‐γ, IL‐2, and GM‐CSF have shown stronger efficacy than BCG alone in inducing anti‐tumour responses and preventing recurrence in patients with bladder cancer 201 . IFN‐γ 202‐204 and GM‐CSF 165,166 are both known to enhance anti‐mycobacterial activity by monocytes and macrophages, and are also essential for the induction of trained immunity at the level of myeloid precursors in the bone marrow in murine models 150,163,164 . In mice, BCG strains expressing GM‐CSF have been shown to increase the quantity of pulmonary APCs compared to BCG alone, leading to enhanced T cell responses and improved protection against disseminated Mtb infection 205,206 .…”

Cytokine/Chemokine Release Patterns and Transcriptomic Profiles of LPS/IFNγ-Activated Human Macrophages Differentiated with Heat-Killed Mycobacterium obuense, M-CSF, or GM-CSF

“…Upstream regulator analysis identified colony-stimulating factor 2 (CSF2; also known as GM-CSF) as the top activated upstream regulator in Mob-(LPS/IFNγ) compared with both M-MDM(LPS/IFNγ) and GM-MDM(LPS/IFNγ). GM-CSF has been previously reported to play a pivotal role in controlling M. tuberculosis infection in human MDMs in vitro, whereby the degree of infection control was positively correlated with GM-CSF secreted levels and with activated GM-CSF signaling pathways in infected Mϕs [60,61]. Further studies are clearly warranted to evaluate the antimycobacterial properties of Mob-MDM(LPS/IFNγ).…”

Probiotic-Based Therapy for Active Tuberculosis Infection: The Role of Gut-Lung Axis and Granulocyte Macrophage-Colony Stimulating Factor

“…When tuberculosis infection occurs, the gut microbiota will stimulate different immune cells, such as mucosaassociated invariant T (MAIT) cells, group 3 innate lymphoid cells (ILC3), and natural killer (NK) cells to induce protective immunity in the lungs. 26 The mechanism of gut microbiota against tuberculosis infection through GM-CSF activation [26][27][28][29]…”

“…Figure 2. The mechanism of gut microbiota against tuberculosis infection through GM-CSF activation[26][27][28][29] …”