insight - Immunology - # Neutrophil-derived IL-17 and its role in tuberculosis pathogenesis

Neutrophils Serve as a Permissive Niche for Mycobacterium tuberculosis, Promoting Disease Pathogenesis through an IL-17-Dependent Mechanism

Q: How do the metabolic and functional characteristics of neutrophils contribute to their ability to serve as a permissive niche for Mtb?

Neutrophils, particularly the Ly6G+ granulocyte subset, exhibit unique metabolic and functional characteristics that enable them to serve as a permissive niche for Mycobacterium tuberculosis (Mtb). These characteristics include their ability to undergo metabolic reprogramming during infection, which allows them to adapt to the presence of intracellular pathogens. Neutrophils primarily rely on glycolysis for energy production, which supports their rapid response to infection. This metabolic flexibility enables them to survive and proliferate even in the presence of Mtb, which can evade immune responses. Functionally, neutrophils are equipped with various mechanisms that can both combat and inadvertently support Mtb survival. They produce reactive oxygen species (ROS) and antimicrobial peptides that are typically effective against pathogens. However, Mtb has evolved strategies to resist these attacks, allowing it to persist within neutrophils. Additionally, neutrophils can secrete cytokines such as IL-17, which further enhances their own recruitment and activation, creating a feedback loop that exacerbates inflammation and supports Mtb survival. The presence of COX2 and the production of prostaglandins (PGE2) in neutrophils also play a role in modulating the immune response, potentially leading to an environment that favors Mtb persistence. Thus, the metabolic and functional characteristics of neutrophils not only facilitate their role in the immune response but also contribute to their capacity to harbor Mtb, making them a significant niche for the pathogen.

Q: What are the potential mechanisms by which targeting the IL-17-COX2-neutrophil axis could enhance the protective efficacy of the BCG vaccine?

Targeting the IL-17-COX2-neutrophil axis presents several potential mechanisms to enhance the protective efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB). First, by neutralizing IL-17 or inhibiting COX2, the recruitment and infiltration of Ly6G+ granulocytes can be significantly reduced. This reduction in neutrophil numbers in the lungs can decrease the overall bacterial burden, as these cells are a major reservoir for Mtb. Second, inhibiting COX2 can lead to a shift in the arachidonic acid metabolism from prostaglandin production towards leukotriene synthesis, which has been associated with protective immune responses. This metabolic shift can enhance the recruitment of other immune cells, such as macrophages and T cells, which are more effective at controlling Mtb compared to neutrophils. Third, targeting this axis can also reduce the inflammatory environment that is often detrimental to effective immune responses. High levels of IL-17 and PGE2 can lead to excessive inflammation, which may impair the function of other immune cells. By modulating this inflammatory response, the BCG vaccine can elicit a more balanced and effective immune response, improving its overall efficacy. Finally, the combination of IL-17 neutralization and COX2 inhibition has been shown to synergistically reduce the Mtb burden in both the lungs and the systemic circulation, thereby enhancing the overall protective effect of the BCG vaccine. This multifaceted approach not only targets the immediate bacterial load but also optimizes the immune environment for a more robust and sustained response against TB.

Q: Could modulating the neutrophil-derived IL-17 response be a viable strategy for host-directed therapy in other chronic infectious diseases beyond tuberculosis?

Yes, modulating the neutrophil-derived IL-17 response could be a viable strategy for host-directed therapy in other chronic infectious diseases beyond tuberculosis. The role of IL-17 in chronic inflammation and immune responses is well-documented, and its dysregulation is implicated in various chronic infections and inflammatory diseases. In conditions such as chronic viral infections (e.g., HIV, hepatitis), autoimmune diseases, and even certain fungal infections, elevated levels of IL-17 have been associated with exacerbated pathology and poor clinical outcomes. By targeting the IL-17 response, it may be possible to reduce inflammation and tissue damage, thereby improving patient outcomes. Furthermore, neutrophils are often among the first responders to infections and play a critical role in shaping the immune response. Their ability to produce IL-17 can influence the recruitment and activation of other immune cells, such as T cells and macrophages. Therefore, modulating this response could help restore a more balanced immune environment, promoting effective pathogen clearance while minimizing tissue damage. In summary, targeting the neutrophil-derived IL-17 response holds promise as a therapeutic strategy in various chronic infectious diseases, potentially leading to improved management of these conditions by enhancing the host's immune response while mitigating harmful inflammation.

Core Concepts

Neutrophils (Ly6G+ granulocytes) serve as a major niche for Mycobacterium tuberculosis (Mtb) in the lungs, and their IL-17 production establishes a pro-pathogenic axis that exacerbates tuberculosis disease.

Abstract

The study investigates the role of neutrophils (Ly6G+ granulocytes) in tuberculosis (TB) pathogenesis. Key findings:

Neutrophils harbor the highest intracellular burden of Mtb compared to other immune cell types like macrophages and mesenchymal stem cells in the lungs of Mtb-infected mice, even in BCG-vaccinated animals.
In genetically susceptible IFNγ-/- mice, excessive neutrophil infiltration and their resident Mtb burden correlate with severe disease pathology and mortality.
Neutrophils, rather than Th17 cells, are the major source of IL-17 in the lungs of Mtb-infected mice, both in wild-type and IFNγ-/- backgrounds.
Neutralizing IL-17 and inhibiting COX2 (to block PGE2 production) reverse the neutrophil-driven pathology in IFNγ-/- mice.
In wild-type mice, targeting the IL-17-COX2-neutrophil axis, either by inhibiting RORγt (the key transcription factor for IL-17) or COX2, reduces the neutrophil-resident Mtb burden and enhances the protective efficacy of the BCG vaccine.
In human pulmonary TB patients, high neutrophil counts and IL-17 levels at the time of diagnosis correlate with adverse treatment outcomes.

Together, the results highlight the detrimental role of the IL-17-neutrophil axis in TB pathogenesis and suggest targeting this axis as a potential host-directed therapeutic strategy.

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biorxiv.org

Stats

Mtb burden in Ly6G+ granulocytes is 4-5 times higher than in macrophages or mesenchymal stem cells in the lungs of infected mice.
Mtb-infected IFNγ-/- mice show a nearly 40-fold higher number of Ly6G+ granulocytes compared to infected wild-type mice.
Mtb-infected IFNγ-/- mice have significantly higher levels of IL-17, CXCL1, CXCL2, IL-1β, IL-1α, IL-6, M-CSF, CCL3, and TNFα in the lungs compared to infected wild-type mice.
Pulmonary TB patients with treatment failure have significantly higher serum IL-17 levels and blood neutrophil counts compared to those who were successfully cured.

Quotes

"Neutrophils serve as a preferred niche for Mtb to withstand host immunological assaults in mice."
"Ly6G+ granulocytes still contained 10-20-fold more bacilli compared to the other two cell types (macrophages and mesenchymal stem cells) for each time point post-infection in BCG-vaccinated animals."
"Combining IL-17 neutralization with COX2 inhibition showed better Mtb control in the IFNγ-/- mice."

Key Insights Distilled From

Ly6G+Granulocytes-derived IL-17 limits protective host responses and promotes tuberculosis pathogenesis

by Sharma,P., S... at www.biorxiv.org 10-06-2023

https://www.biorxiv.org/content/10.1101/2023.10.05.561061v2

Deeper Inquiries

How do the metabolic and functional characteristics of neutrophils contribute to their ability to serve as a permissive niche for Mtb?

Neutrophils, particularly the Ly6G+ granulocyte subset, exhibit unique metabolic and functional characteristics that enable them to serve as a permissive niche for Mycobacterium tuberculosis (Mtb). These characteristics include their ability to undergo metabolic reprogramming during infection, which allows them to adapt to the presence of intracellular pathogens. Neutrophils primarily rely on glycolysis for energy production, which supports their rapid response to infection. This metabolic flexibility enables them to survive and proliferate even in the presence of Mtb, which can evade immune responses.
Functionally, neutrophils are equipped with various mechanisms that can both combat and inadvertently support Mtb survival. They produce reactive oxygen species (ROS) and antimicrobial peptides that are typically effective against pathogens. However, Mtb has evolved strategies to resist these attacks, allowing it to persist within neutrophils. Additionally, neutrophils can secrete cytokines such as IL-17, which further enhances their own recruitment and activation, creating a feedback loop that exacerbates inflammation and supports Mtb survival. The presence of COX2 and the production of prostaglandins (PGE2) in neutrophils also play a role in modulating the immune response, potentially leading to an environment that favors Mtb persistence. Thus, the metabolic and functional characteristics of neutrophils not only facilitate their role in the immune response but also contribute to their capacity to harbor Mtb, making them a significant niche for the pathogen.

What are the potential mechanisms by which targeting the IL-17-COX2-neutrophil axis could enhance the protective efficacy of the BCG vaccine?

Targeting the IL-17-COX2-neutrophil axis presents several potential mechanisms to enhance the protective efficacy of the Bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB). First, by neutralizing IL-17 or inhibiting COX2, the recruitment and infiltration of Ly6G+ granulocytes can be significantly reduced. This reduction in neutrophil numbers in the lungs can decrease the overall bacterial burden, as these cells are a major reservoir for Mtb.
Second, inhibiting COX2 can lead to a shift in the arachidonic acid metabolism from prostaglandin production towards leukotriene synthesis, which has been associated with protective immune responses. This metabolic shift can enhance the recruitment of other immune cells, such as macrophages and T cells, which are more effective at controlling Mtb compared to neutrophils.
Third, targeting this axis can also reduce the inflammatory environment that is often detrimental to effective immune responses. High levels of IL-17 and PGE2 can lead to excessive inflammation, which may impair the function of other immune cells. By modulating this inflammatory response, the BCG vaccine can elicit a more balanced and effective immune response, improving its overall efficacy.
Finally, the combination of IL-17 neutralization and COX2 inhibition has been shown to synergistically reduce the Mtb burden in both the lungs and the systemic circulation, thereby enhancing the overall protective effect of the BCG vaccine. This multifaceted approach not only targets the immediate bacterial load but also optimizes the immune environment for a more robust and sustained response against TB.

Could modulating the neutrophil-derived IL-17 response be a viable strategy for host-directed therapy in other chronic infectious diseases beyond tuberculosis?

Yes, modulating the neutrophil-derived IL-17 response could be a viable strategy for host-directed therapy in other chronic infectious diseases beyond tuberculosis. The role of IL-17 in chronic inflammation and immune responses is well-documented, and its dysregulation is implicated in various chronic infections and inflammatory diseases.
In conditions such as chronic viral infections (e.g., HIV, hepatitis), autoimmune diseases, and even certain fungal infections, elevated levels of IL-17 have been associated with exacerbated pathology and poor clinical outcomes. By targeting the IL-17 response, it may be possible to reduce inflammation and tissue damage, thereby improving patient outcomes.
Furthermore, neutrophils are often among the first responders to infections and play a critical role in shaping the immune response. Their ability to produce IL-17 can influence the recruitment and activation of other immune cells, such as T cells and macrophages. Therefore, modulating this response could help restore a more balanced immune environment, promoting effective pathogen clearance while minimizing tissue damage.
In summary, targeting the neutrophil-derived IL-17 response holds promise as a therapeutic strategy in various chronic infectious diseases, potentially leading to improved management of these conditions by enhancing the host's immune response while mitigating harmful inflammation.