Elevated procoagulant platelets driven by necroptosis and pyroptosis aggravate pulmonary thrombosis via suppressing monocyte efferocytosis in severe pneumonia
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
BACKGROUND
Severe influenza pneumonia with secondary bacterial infection is complicated by progressive pulmonary thrombus exacerbation, a key contributor to respiratory failure, yet anticoagulant therapies show limited efficacy and bleeding risks. Although platelet-monocyte crosstalk initiates thrombosis, whether and how it drives thrombus exacerbation via procoagulant platelets and monocyte efferocytosis remains unclear.
METHODS
Clinical samples, mouse models, and isolated platelets challenged with influenza A virus followed by methicillin-resistant Staphylococcus aureus (MRSA) were analyzed. Procoagulant platelet, platelet programmed cell death and monocyte efferocytosis were assessed, and pharmacological inhibition, platelet depletion and systemic/platelet-specific Gsdmd knockout were used. Platelet proteomics and exogenous C1qa supplementation identified C1qa as a key mediator.
RESULTS
We showed that elevated procoagulant platelet-driven thrombus exacerbation, rather than initial thrombus formation, was a critical driver of disease progression in influenza pneumonia with secondary bacterial infection, whereas influenza alone caused milder illness. Procoagulant platelet formation was induced via MLKL-mediated necroptosis and GSDMD-mediated pyroptosis. These platelets exacerbated pulmonary thrombosis and lung injury by inhibiting monocyte efferocytosis via complement C1qa. Platelet depletion reduced monocyte efferocytosis and worsened pneumonia, while pharmacological inhibition or platelet-specific Gsdmd knockout decreased procoagulant platelet levels, restored monocyte efferocytosis, and alleviated thrombotic and pulmonary injury. Mechanistically, C1qa impaired efferocytosis both by directly suppressing monocyte function and by reducing the proportion of reparative (M2-like) monocytes. Clinical relevance was confirmed by detection of MLKL/GSDMD-dependent procoagulant platelets and reduced efferocytosis receptor levels on monocytes in bronchoalveolar lavage fluid from severe pneumonia patients.
CONCLUSIONS
Necroptosis/pyroptosis-driven procoagulant platelets exacerbate pulmonary thrombosis by suppressing monocyte efferocytosis in a C1qa-dependent manner. These findings extend platelet-monocyte crosstalk from thrombus initiation to thrombus exacerbation, identifying modulation of the interaction between procoagulant platelets and monocyte efferocytosis as a potential therapeutic strategy for thrombus-exacerbating diseases, especially in subpopulations of patients with severe pneumonia and progressive pulmonary thrombosis.
What Is Known?
Pulmonary thrombus exacerbation are hallmarks of severe influenza pneumonia complicated by secondary or concurrent bacterial infection, but are absent in uncomplicated mild influenza pneumonia.
Procoagulant platelets are key mediators of thrombotic and thromboinflammatory diseases.
The platelet-monocyte crosstalk via P-selectin/PSGL-1 and CD40L/CD40 initiates thrombosis, whereas the mechanisms driving progressive thrombus exacerbation remain unknown in severe pneumonia.
What New Information Does This Article Contribute?
Necroptosis- and pyroptosis-driven elevation of procoagulant platelets mediates thrombus exacerbation, representing a key pathological feature of severe pneumonia.
Procoagulant platelet-impaired monocyte efferocytosis crosstalk drives thrombus exacerbation, shifting the focus from thrombus initiation to progression and offering new insight into platelet-monocyte interactions in thrombotic disease.
Complement C1qa may be a key mediator linking procoagulant platelets to impaired monocyte efferocytosis.
Severe influenza pneumonia with secondary bacterial infection is complicated by pulmonary thrombus exacerbation, a key contributor to respiratory failure. Although platelet-monocyte crosstalk has been implicated in thrombus initiation, whether and how this crosstalk aggravates thrombosis remains unclear. Using clinical samples, mouse models and isolated platelets challenged with influenza A virus followed by MRSA, this study shows that MLKL-mediated necroptosis and GSDMD-mediated pyroptosis promote procoagulant platelet formation. These procoagulant platelets inhibit monocyte efferocytosis via complement C1qa, thereby exacerbating pulmonary thrombosis and lung injury. Clinical relevance is confirmed by MLKL/GSDMD-dependent procoagulant platelets and reduced efferocytosis receptor levels on monocytes in BALF from severe pneumonia patients. Collectively, these findings extend platelet-monocyte crosstalk from thrombus initiation to thrombus exacerbation, identifying modulation of the interaction between procoagulant platelets and monocyte efferocytosis as a potential therapeutic strategy for thrombus-exacerbating diseases.
