통찰 - Immunology Tuberculosis - # Dendritic cell metabolism and migration in tuberculosis

Mycobacterium tuberculosis Infection Impairs Dendritic Cell Migration by Disrupting Glycolytic Metabolism

Q: How do the metabolic alterations in monocytes from tuberculosis patients impact the function and phenotype of other immune cell types, such as T cells and macrophages?

The metabolic alterations observed in monocytes from tuberculosis (TB) patients can have significant impacts on the function and phenotype of other immune cell types. Monocytes from TB patients exhibit an exacerbated glycolytic activity, leading to the generation of dendritic cells (DCs) with poor migratory capacities. This impaired migration of DCs can hinder the activation of T cells, as DCs play a crucial role in presenting antigens to T cells and initiating immune responses. The delayed migration of DCs from the site of infection to the draining lymph nodes in TB patients can result in a delayed or weakened T cell response, affecting the development of protective immunity against Mycobacterium tuberculosis. Furthermore, the altered metabolic state of monocytes in TB patients may also impact the function of macrophages. Macrophages are key players in the immune response to TB, involved in phagocytosis and killing of M. tuberculosis. The dysregulated glycolytic activity in monocytes could potentially lead to the generation of macrophages with altered functions, such as impaired phagocytosis or reduced antimicrobial activity. This could contribute to the persistence of M. tuberculosis infection and the progression of TB disease in patients. In summary, the metabolic alterations in monocytes from TB patients can have cascading effects on the function and phenotype of other immune cell types, including T cells and macrophages, ultimately impacting the overall immune response to M. tuberculosis infection.

Q: How can the potential mechanisms by which the glycolytic state of monocytes is maintained in tuberculosis patients be therapeutically targeted?

The maintenance of the glycolytic state in monocytes from tuberculosis (TB) patients presents a potential therapeutic target for improving immune responses and outcomes in TB. Several mechanisms may contribute to the dysregulated glycolytic activity in monocytes from TB patients, including chronic inflammation, altered signaling pathways, and metabolic reprogramming induced by Mycobacterium tuberculosis (Mtb) infection. To therapeutically target the glycolytic state of monocytes in TB patients, the following strategies could be considered: Targeting TLR2 Signaling: Since TLR2 ligation by Mtb triggers glycolysis in monocytes, modulating TLR2 signaling pathways could be a potential therapeutic approach. Developing TLR2 inhibitors or modulators could help regulate the excessive glycolytic activity in monocytes from TB patients. Metabolic Modulators: Using metabolic modulators that target glycolysis pathways could be another strategy. Inhibitors of glycolysis enzymes or activators of oxidative phosphorylation could help restore the metabolic balance in monocytes from TB patients. HIF-1α Inhibition: Since HIF-1α is a key regulator of glycolysis, targeting HIF-1α activity could be a promising therapeutic approach. Inhibitors of HIF-1α, such as PX-478, could be used to modulate the glycolytic state of monocytes and potentially improve their function and differentiation into immune cells. Immunomodulatory Therapies: Immunomodulatory therapies that target the inflammatory microenvironment in TB patients could also impact the glycolytic state of monocytes. Anti-inflammatory agents or immune-modulating drugs may help regulate the metabolic alterations in monocytes and improve immune responses. By targeting the mechanisms that maintain the glycolytic state in monocytes from TB patients, it may be possible to restore normal metabolic function, enhance immune responses, and potentially improve outcomes in TB.

Q: Could modulating the metabolic state of dendritic cells at the site of Mycobacterium tuberculosis infection, rather than in the periphery, further enhance their migratory and functional capacities?

Modulating the metabolic state of dendritic cells (DCs) at the site of Mycobacterium tuberculosis (Mtb) infection, rather than in the periphery, could indeed enhance their migratory and functional capacities. DCs play a critical role in initiating immune responses by presenting antigens to T cells and activating them. The migration of DCs from the site of infection to the draining lymph nodes is essential for the development of protective immunity against Mtb. By targeting the metabolic state of DCs at the infection site, several benefits can be achieved: Enhanced Migration: Modulating the metabolic state of DCs at the infection site can promote their migratory capacities. By increasing glycolysis or stabilizing HIF-1α activity in DCs, their ability to migrate to the draining lymph nodes in response to chemotactic signals, such as CCL21, can be improved. This enhanced migration can lead to more efficient antigen presentation and T cell activation. Improved Functionality: Altering the metabolic state of DCs at the infection site can also enhance their functional capacities. Metabolically active DCs are better equipped to process and present antigens, secrete cytokines, and interact with T cells. By promoting glycolysis or HIF-1α activation in DCs, their immunogenic functions can be enhanced, leading to a more robust immune response against Mtb. Targeted Immune Activation: By modulating the metabolic state of DCs specifically at the infection site, it is possible to target immune activation in a localized manner. This targeted approach can optimize the immune response against Mtb, focusing on the areas where DC-T cell interactions are crucial for effective immunity. In conclusion, modulating the metabolic state of DCs at the site of Mtb infection can have significant benefits in enhancing their migratory and functional capacities, ultimately improving the immune response and outcomes in tuberculosis.

핵심 개념

Mycobacterium tuberculosis infection triggers a glycolytic metabolic profile in dendritic cells, which is essential for their migration to lymph nodes. However, the glycolytic state of monocytes from tuberculosis patients impairs the ability of derived dendritic cells to migrate in response to Mycobacterium tuberculosis.

초록

The content explores the impact of Mycobacterium tuberculosis (Mtb) infection on the metabolism and migratory capacity of human monocyte-derived dendritic cells (Mo-DCs).

Key highlights:

Mtb exposure triggers aerobic glycolysis in Mo-DCs, as evidenced by increased lactate release, glucose consumption, and expression of glycolytic genes like HIF-1α and LDHA.
The glycolytic shift in Mo-DCs is mediated through TLR2 ligation by Mtb.
Inhibition of HIF-1α-driven glycolysis impairs the migration of iMtb-stimulated Mo-DCs in vitro and in vivo.
Monocytes from tuberculosis patients exhibit an inherent glycolytic bias, which leads to the generation of Mo-DCs with poor glycolytic and migratory capacities in response to Mtb.
Stabilizing HIF-1α can restore the migratory defects of tolerogenic DCs and DCs derived from tuberculosis patient monocytes.

The data suggests that the metabolic state of monocyte precursors, particularly the glycolytic profile, is a critical determinant of the migratory capacity of DCs during Mtb infection. Modulating the metabolic pathways in DCs may represent a potential strategy to enhance their trafficking and improve tuberculosis vaccine efficacy.

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biorxiv.org

통계

Mtb infection increases lactate release and glucose consumption in human monocyte-derived DCs.
Mtb infection upregulates the expression of HIF-1α and LDHA in human monocyte-derived DCs.
Mtb infection increases the expression of the glucose transporter GLUT1 in human monocyte-derived DCs.
Mtb infection increases mitochondrial mass and size in human monocyte-derived DCs.
Inhibition of HIF-1α or glycolysis reduces the migration of iMtb-stimulated human monocyte-derived DCs in vitro and in vivo.
Monocytes from tuberculosis patients exhibit higher baseline glycolytic capacity compared to healthy subjects.
The glycolytic capacity of CD16+ monocytes from tuberculosis patients correlates with the duration of tuberculosis symptoms.

인용구

"Mtb exposure triggers glycolysis in Mo-DCs from healthy donors, which promotes their migration capacity in a HIF-1α-dependent manner."
"The activated glycolytic status of monocytes from TB patients leads to the generation of DCs with low motility in response to Mtb."
"An increase in HIF1α-mediated glycolysis in precursors leads to the generation of cells with poor ability to migrate in response to CCL21 in vitro."

핵심 통찰 요약

Elevated glycolytic metabolism of monocytes limits the generation of HIF-1α-driven migratory dendritic cells in tuberculosis

by Maio... 게시일 www.biorxiv.org 04-07-2023

https://www.biorxiv.org/content/10.1101/2023.04.03.535400v4

더 깊은 질문

How do the metabolic alterations in monocytes from tuberculosis patients impact the function and phenotype of other immune cell types, such as T cells and macrophages?

The metabolic alterations observed in monocytes from tuberculosis (TB) patients can have significant impacts on the function and phenotype of other immune cell types. Monocytes from TB patients exhibit an exacerbated glycolytic activity, leading to the generation of dendritic cells (DCs) with poor migratory capacities. This impaired migration of DCs can hinder the activation of T cells, as DCs play a crucial role in presenting antigens to T cells and initiating immune responses. The delayed migration of DCs from the site of infection to the draining lymph nodes in TB patients can result in a delayed or weakened T cell response, affecting the development of protective immunity against Mycobacterium tuberculosis.
Furthermore, the altered metabolic state of monocytes in TB patients may also impact the function of macrophages. Macrophages are key players in the immune response to TB, involved in phagocytosis and killing of M. tuberculosis. The dysregulated glycolytic activity in monocytes could potentially lead to the generation of macrophages with altered functions, such as impaired phagocytosis or reduced antimicrobial activity. This could contribute to the persistence of M. tuberculosis infection and the progression of TB disease in patients.
In summary, the metabolic alterations in monocytes from TB patients can have cascading effects on the function and phenotype of other immune cell types, including T cells and macrophages, ultimately impacting the overall immune response to M. tuberculosis infection.

How can the potential mechanisms by which the glycolytic state of monocytes is maintained in tuberculosis patients be therapeutically targeted?

The maintenance of the glycolytic state in monocytes from tuberculosis (TB) patients presents a potential therapeutic target for improving immune responses and outcomes in TB. Several mechanisms may contribute to the dysregulated glycolytic activity in monocytes from TB patients, including chronic inflammation, altered signaling pathways, and metabolic reprogramming induced by Mycobacterium tuberculosis (Mtb) infection. To therapeutically target the glycolytic state of monocytes in TB patients, the following strategies could be considered:

Targeting TLR2 Signaling: Since TLR2 ligation by Mtb triggers glycolysis in monocytes, modulating TLR2 signaling pathways could be a potential therapeutic approach. Developing TLR2 inhibitors or modulators could help regulate the excessive glycolytic activity in monocytes from TB patients.

Metabolic Modulators: Using metabolic modulators that target glycolysis pathways could be another strategy. Inhibitors of glycolysis enzymes or activators of oxidative phosphorylation could help restore the metabolic balance in monocytes from TB patients.

HIF-1α Inhibition: Since HIF-1α is a key regulator of glycolysis, targeting HIF-1α activity could be a promising therapeutic approach. Inhibitors of HIF-1α, such as PX-478, could be used to modulate the glycolytic state of monocytes and potentially improve their function and differentiation into immune cells.

Immunomodulatory Therapies: Immunomodulatory therapies that target the inflammatory microenvironment in TB patients could also impact the glycolytic state of monocytes. Anti-inflammatory agents or immune-modulating drugs may help regulate the metabolic alterations in monocytes and improve immune responses.

By targeting the mechanisms that maintain the glycolytic state in monocytes from TB patients, it may be possible to restore normal metabolic function, enhance immune responses, and potentially improve outcomes in TB.

Could modulating the metabolic state of dendritic cells at the site of Mycobacterium tuberculosis infection, rather than in the periphery, further enhance their migratory and functional capacities?

Modulating the metabolic state of dendritic cells (DCs) at the site of Mycobacterium tuberculosis (Mtb) infection, rather than in the periphery, could indeed enhance their migratory and functional capacities. DCs play a critical role in initiating immune responses by presenting antigens to T cells and activating them. The migration of DCs from the site of infection to the draining lymph nodes is essential for the development of protective immunity against Mtb. By targeting the metabolic state of DCs at the infection site, several benefits can be achieved:

Enhanced Migration: Modulating the metabolic state of DCs at the infection site can promote their migratory capacities. By increasing glycolysis or stabilizing HIF-1α activity in DCs, their ability to migrate to the draining lymph nodes in response to chemotactic signals, such as CCL21, can be improved. This enhanced migration can lead to more efficient antigen presentation and T cell activation.

Improved Functionality: Altering the metabolic state of DCs at the infection site can also enhance their functional capacities. Metabolically active DCs are better equipped to process and present antigens, secrete cytokines, and interact with T cells. By promoting glycolysis or HIF-1α activation in DCs, their immunogenic functions can be enhanced, leading to a more robust immune response against Mtb.

Targeted Immune Activation: By modulating the metabolic state of DCs specifically at the infection site, it is possible to target immune activation in a localized manner. This targeted approach can optimize the immune response against Mtb, focusing on the areas where DC-T cell interactions are crucial for effective immunity.

In conclusion, modulating the metabolic state of DCs at the site of Mtb infection can have significant benefits in enhancing their migratory and functional capacities, ultimately improving the immune response and outcomes in tuberculosis.