biostudies-literatureMizuno TResearch Center for Pathogenesis of Intractable Diseases, Research Institute of Meijo UniversityMinistry of Education, Culture, Science, and TechnologyJapan Society for the Promotion of Science574-583https://www.ebi.ac.uk/biostudies/studies/S-EPMC10988669biostudies-literatureUnknown14(4)Acute lung injury (ALI), which occurs in association with sepsis, trauma, and coronavirus disease 2019 (COVID-19), is a serious clinical condition with high mortality. Excessive platelet-leukocyte aggregate (PLA) formation promotes neutrophil extracellular trap (NET) release and thrombosis, which are involved in various diseases, including ALI. Macrophage-1 antigen (Mac-1, CD11b/CD18), which is expressed on the surface of leukocytes, is known to promote NET formation. This study aimed to elucidate the role of Mac-1 in extracellular histone-induced ALI. Exogenous histones were administered to Mac-1-deficient mice and wild-type (WT) mice with or without neutrophil or platelet depletion, and several parameters were investigated 1 h after histone injection. Depletion of neutrophils or platelets improved survival time and macroscopic and microscopic properties of lung tissues, and decreased platelet-leukocyte formation and plasma myeloperoxidase levels. These improvements were also observed in Mac-1^-/- mice. NET formation in Mac-1^-/- bone marrow neutrophils (BMNs) was significantly lower than that in WT BMNs. In conclusion, our findings suggest that Mac-1 is associated with exacerbation of histone-induced ALI and the promotion of NET formation in the presence of activated platelets.FEBS open bioMacrophage-1 antigen exacerbates histone-induced acute lung injury and promotes neutrophil extracellular trap formation.PMC1098866919K0723221K0669620J22610Mizuno TNagano FFruhashi KYamada STsuboi NTakahashi KMaruyama SfalseMacrophage-1 antigen exacerbates histone-induced acute lung injury and promotes neutrophil extracellular trap formation.Acute lung injury (ALI), which occurs in association with sepsis, trauma, and coronavirus disease 2019 (COVID-19), is a serious clinical condition with high mortality. Excessive platelet-leukocyte aggregate (PLA) formation promotes neutrophil extracellular trap (NET) release and thrombosis, which are involved in various diseases, including ALI. Macrophage-1 antigen (Mac-1, CD11b/CD18), which is expressed on the surface of leukocytes, is known to promote NET formation. This study aimed to elucidate the role of Mac-1 in extracellular histone-induced ALI. Exogenous histones were administered to Mac-1-deficient mice and wild-type (WT) mice with or without neutrophil or platelet depletion, and several parameters were investigated 1 h after histone injection. Depletion of neutrophils or platelets improved survival time and macroscopic and microscopic properties of lung tissues, and decreased platelet-leukocyte formation and plasma myeloperoxidase levels. These improvements were also observed in Mac-1^-/- mice. NET formation in Mac-1^-/- bone marrow neutrophils (BMNs) was significantly lower than that in WT BMNs. In conclusion, our findings suggest that Mac-1 is associated with exacerbation of histone-induced ALI and the promotion of NET formation in the presence of activated platelets.2024-01-01T00:00:00Z2024 Apr2025-04-18T20:13:30.768Z2025-04-07T08:07:17.189ZS-EPMC109886693836005710.1002/2211-5463.13779