Platelet-leucocyte interactions drive MMP-mediated tissue damage in tuberculosis

Area of Science:

• Immunology
• Pulmonology
• Pathology

Background:

• Tuberculosis (TB) involves inflammation and matrix metalloproteinase (MMP) activity, leading to tissue damage.
• Platelets are increasingly recognized as key inflammatory drivers.
• Platelet-leukocyte aggregates, particularly involving monocyte PSGL-1 and platelet P-selectin, may mediate TB-related tissue destruction.

Purpose of the Study:

• To investigate the role of platelet-leukocyte interactions in tuberculosis pathogenesis.
• To assess the impact of these interactions on MMP secretion and gene expression.
• To explore potential host-directed therapeutic targets in TB.

Main Methods:

• Utilized a platelet-monocyte co-culture model to study interactions.
• Examined M.tb-infected and control lymph node tissue via immunofluorescence microscopy.
• Quantified platelet aggregation, platelet-monocyte aggregates (PMA), platelet-neutrophil aggregates (PNA), and receptor expression in TB patients, healthy controls, and respiratory symptomatic patients using flow cytometry and light transmission aggregometry.

Main Results:

• M.tb-infected monocytes co-cultured with platelets showed significantly increased MMP-1 and MMP-10 secretion and mmp1 gene expression.
• MMP-1 secretion was enhanced by platelet-derived soluble factors and monocyte PSGL-1 ligation.
• Abundant platelets were found in M.tb-infected lymph nodes, localizing to monocytic PSGL-1, unlike in controls.
• Ex vivo platelet aggregation was reduced in TB patients compared to healthy controls.
• PMA levels were elevated in TB and respiratory symptomatic patients, while PNA levels were higher only in TB patients.
• Platelet P-selectin expression, PMA, and PNA correlated, independent of GPIIb/IIIa, suggesting a non-thrombotic pathway.

Conclusions:

• PSGL-1/P-selectin mediated platelet-leukocyte interactions are crucial drivers of inflammation and MMP secretion in pulmonary TB.
• Platelets are significant regulators of tissue-damaging inflammatory responses in tuberculosis.
• Targeting platelet-leukocyte interactions presents a promising host-directed therapeutic strategy for TB and potentially other lung diseases.