Biology subjects

Hamad, M. A.

Publications and source records attributed to Hamad, M. A..

2 recordsLinked to original sources

bioRxiv2026

Platelet C5aR1 Aggravates Myocardial Infarction through Platelet-Neutrophil Interactions and CXCL4-Dependent NET Release

Platelet activation is a central driver of myocardial infarction. The complement anaphylatoxin C5a is abundantly generated during myocardial infarction, and its receptor C5aR1 is highly expressed on platelets. However, the functional role of platelet C5aR1 in myocardial infarction (MI) remains unknown. Here, we show that platelet&[ndash]expressed C5aR1 critically amplifies thromboinflammatory cardiac injury by promoting platelet&[ndash]mediated neutrophil activation after MI. Platelet&[ndash]specific C5aR1 deletion reduced infarct size, fibrosis, and adverse remodeling while enhancing neovascularization and preserving cardiac function. Mechanistically, cell&[ndash]specific C5aR1 deletion markedly reduced myocardial platelet&[ndash]neutrophil accumulation and neutrophil extracellular trap (NET) formation, while circulating platelet&[ndash]neutrophil complexes were increased. Ex vivo, C5a&[ndash]stimulated platelets robustly induced NET release from neutrophils in a platelet C5aR1&[ndash] and CXCL4&[ndash]dependent manner, whereas platelets lacking C5aR1 failed to trigger NET formation. Pharmacological C5aR1 inhibition with PMX205 phenocopied the genetic platelet&[ndash]specific deletion, resulting in comparable cardioprotection. Together, these findings identify platelet C5aR1 as a druggable target of platelet&[ndash]neutrophil&[ndash]NET signaling that exacerbates myocardial injury and limits reparative healing after MI, highlighting platelet C5aR1 as a potential therapeutic approach to restrain thromboinflammation.

immunology↗

bioRxiv2023

The Achromobacter Type 3 secretion system drives pyroptosis and immunopathology via independent activation of NLRC4 and NLRP3 inflammasomes

Achromobacter species are newly recognized opportunistic, pro-inflammatory Gram-negative pathogens in immunocompromised individuals, but how they interact with the innate immune system to drive inflammation is poorly understood. We created sctV (Type 3 Secretion System baseplate) mutants in three Achromobacter clinical isolates from two species and showed that all three required the T3SS to induce cell death in human macrophages. Mutating other critical T3SS components also abolished cell death, which was restored by genetic complementation. Cell death of Achromobacter-infected macrophages was contact-dependent, enhanced by bacterial internalisation, and caused by inflammasome-dependent pyroptosis (typified by Gasdermin-D cleavage and IL-1{beta} secretion). Macrophages deficient in the inflammasome sensors NLRC4 or NLRP3 underwent pyroptosis upon bacterial internalization but those deficient in both NLRC4 and NLRP3 did not, suggesting either sensor can mediate pyroptosis induction in a T3SS-dependent manner. Detailed analysis of the intracellular trafficking of one isolate indicated that the intracellular bacteria reside in an acidic LAMP-1/dextran-positive membrane compartment. Using an intranasal mouse infection model, we observed that Achromobacter damages lung structure and causes severe illness, contingent on a functional T3SS. Together, we demonstrate that Achromobacter species can survive phagocytosis by macrophages and promote macrophage cell death and inflammation by redundant mechanisms of pyroptosis induction.

microbiology↗