Myeloid-Derived Suppressor Cells as Target of Phosphodiesterase-5 Inhibitors in Host-Directed Therapeutics for Tuberculosis

Leukes, Vinzeigh N.; Walzl, Gerhard; Plessis, Nelita du

doi:10.3389/fimmu.2020.00451

Cited by 23 publications

(26 citation statements)

References 66 publications

(68 reference statements)

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“…More recently, this neutrophil-related immunosuppressive function on lymphocytes has been attributed to hyper-segmented subsets ( 7 ) and to the neutrophil-like MDSCs ( 54 , 55 ) (in cancer ( 56 , 57 ), leukaemia ( 58 ) and lately TB ( 9 , 59 ). While the immunosuppressive roles of MDSCs on Mtb pathogenesis are still under investigation, recent experimental models show benefits in limiting their accumulation during TB HDTs ( 25 , 60 ). We suggest that MPO could be protective against TB progression and lung damage.…”

Section: Discussionmentioning

confidence: 99%

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

et al. 2021

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BackgroundThe inflammatory response to Mycobacterium tuberculosis results in variable degrees of lung pathology during active TB (ATB) with central involvement of neutrophils. Little is known about neutrophil-derived mediators and their role in disease severity at baseline and recovery upon TB treatment initiation.Methods107 adults with confirmed pulmonary TB were categorised based on lung pathology at baseline and following successful therapy using chest X-ray scores (Ralph scores) and GeneXpert bacterial load (Ct values). Plasma, sputum, and antigen-stimulated levels of MMP1, MMP3, MMP8, MMP9, MPO, S100A8/9, IL8, IL10, IL12/23(p40), GM-CSF, IFNγ, and TNF were analysed using multiplex cytokine arrays.ResultsAt baseline, neutrophil counts correlated with plasma levels of MMP8 (rho = 0.45, p = 2.80E−06), S100A8 (rho = 0.52, p = 3.00E−08) and GM-CSF (rho = 0.43, p = 7.90E−06). Levels of MMP8 (p = 3.00E−03), MMP1 (p = 1.40E−02), S100A8 (p = 1.80E−02) and IL12/23(p40) (p = 1.00E−02) were associated with severe lung damage, while sputum MPO levels were directly linked to lung damage (p = 1.80E−03), Mtb load (p = 2.10E−02) and lung recovery (p = 2.40E−02). Six months of TB therapy significantly decreased levels of major neutrophil-derived pro-inflammatory mediators: MMP1 (p = 4.90E−12 and p = 2.20E−07), MMP8 (p = 3.40E−14 and p = 1.30E−05) and MMP9 (p = 1.60E−04 and p = 1.50E−03) in plasma and sputum, respectively. Interestingly, following H37Rv whole cell lysate stimulation, S100A8 (p = 2.80E−02), MMP9 (p = 3.60E−02) and MPO (p = 9.10E−03) levels at month 6 were significantly higher compared to baseline. Sputum MMP1 (p = 1.50E−03), MMP3 (p = 7.58E−04), MMP9 (p = 2.60E−02) and TNF (p = 3.80E−02) levels were lower at month 6 compared to baseline in patients with good lung recovery.ConclusionIn this study, patients with severe lung pathology at baseline and persistent lung damage after treatment were associated with higher plasma and sputum levels of major pro-inflammatory neutrophil-derived mediators. Interestingly, low sputum MPO levels were associated with severe lung damage, higher Mtb burden and low recovery. Our data suggest that therapeutic agents which target these mediators should be considered for future studies on biomarkers and host-directed therapeutic approaches against TB-related lung pathology and/or lung recovery.

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Section: Discussionmentioning

confidence: 99%

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

et al. 2021

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“…Given that MDSCs suppress the anti-tumor response, they act as a hindrance to the success of cancer therapy. Current therapeutic strategies targeting MDSCs include elimination, functional inhibition of the MDSC suppressive activity and skewing of myelopoiesis away from the generation of MDSCs (33,45). Recent studies have suggested that abnormal splenic EMH is responsible for generating immunosuppressive MDSCs in tumors (21,46).…”

Section: Discussionmentioning

confidence: 99%

Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation

Tao

Wang

et al. 2021

Front. Immunol.

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Recent studies have demonstrated that splenic extramedullary hematopoiesis (EMH) is an important mechanism for the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissues, and thus contributes to disease progression. Icaritin, a prenylflavonoid derivative from plants of the Epimedium genus, has been implicated as a novel immune-modulator that could prolong the survival of hepatocellular carcinoma (HCC) patients. However, it is unclear whether icaritin achieves its anti-tumor effects via the regulation of MDSCs generated by EMH in HCC. Here, we investigated the anti-tumor potential of icaritin and its mechanism of action in murine HCC. Icaritin suppressed tumor progression and significantly prolonged the survival of mice-bearing orthotopic and subcutaneous HCC tumors. Rather than exerting direct cytotoxic activity against tumor cells, icaritin significantly reduced the accumulation and activation of tumoral and splenic MDSCs, and increased the number and activity of cytotoxic T cells. Mechanistically, icaritin downregulates the tumor-associated splenic EMH, thereby reducing the generation and activation of MDSCs. The inhibitory effects of icaritin on human MDSCs in vitro were verified in short-term culture with cord-blood derived hematopoietic precursors. Furthermore, icaritin synergistically enhanced the therapeutic efficacy of immune checkpoint blockade therapy in HCC mice. These findings revealed that icaritin dampens tumoral immunosuppression to elicit anti-tumor immune responses by preventing MDSC generation via the attenuation of EMH. Thus, icaritin may serve as a novel adjuvant or even a stand-alone therapeutic agent for the effective treatment of HCC.

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“…Sildenafil, an FDA-approved type 5 phosphodiesterase-selective inhibitor (PDE-5i), is used in human patients for the treatment of erectile dysfunction and pulmonary hypertension. The drug downregulates arginase-1 and nitric oxide synthase-2 (NOS2) in a cGMP-dependent fashion, thereby hampering the immunosuppressive potential of MDSCs (110). Maiga et al showed that the combination of sildenafil and cilostazol (an FDA-approved PDE-3 inhibitor) reduced pathology, disease severity and bacterial burden in murine TB; however, monotherapy with sildenafil alone showed no statistically significant benefit in the same mouse model (44,111).…”

Section: Myeloid-derived Suppressor Cells (Mdscs)mentioning

confidence: 99%

Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis

2021

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Following infection with Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), most human hosts are able to contain the infection and avoid progression to active TB disease through expression of a balanced, homeostatic immune response. Proinflammatory mechanisms aiming to kill, slow and sequester the pathogen are key to a successful host response. However, an excessive or inappropriate pro-inflammatory response may lead to granuloma enlargement and tissue damage, which may prolong the TB treatment duration and permanently diminish the lung function of TB survivors. The host also expresses certain anti-inflammatory mediators which may play either beneficial or detrimental roles depending on the timing of their deployment. The balance between the timing and expression levels of pro- and anti-inflammatory responses plays an important role in the fate of infection. Interestingly, M. tuberculosis appears to manipulate both sides of the human immune response to remodel the host environment for its own benefit. Consequently, therapies which modulate either end of this spectrum of immune responses at the appropriate time may have the potential to improve the treatment of TB or to reduce the formation of permanent lung damage after microbiological cure. Here, we highlight host-directed TB therapies targeting pro- or anti-inflammatory processes that have been evaluated in pre-clinical models. The repurposing of already available drugs known to modulate these responses may improve the future of TB therapy.

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Myeloid-Derived Suppressor Cells as Target of Phosphodiesterase-5 Inhibitors in Host-Directed Therapeutics for Tuberculosis

Cited by 23 publications

References 66 publications

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

Major Neutrophil-Derived Soluble Mediators Associate With Baseline Lung Pathology and Post-Treatment Recovery in Tuberculosis Patients

Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation

Host-Directed Therapies: Modulating Inflammation to Treat Tuberculosis

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