Macrophages are important innate immune cells that play crucial roles in inflammatory responses. Accumulating evidence has demonstrated macrophage heterogeneity based on biomarkers, functions, and localization. Here, we report a novel stem cell antigen-1 (Sca-1)-positive macrophage population induced in the pathological conditions caused by lipopolysaccharide (LPS). Sca-1 is only upregulated in macrophages but not in monocytes and neutrophils upon LPS injection. Sca-1(+) macrophages develop from resident peritoneal macrophages. LPS-induced Sca-1(+) macrophage generation was partly blocked by anti-IFN-gamma antibody, suggesting a role of IFN-gamma in the process. LPS-stimulated production of IL-6, THF-alpha, and CCL2 is significantly lower in Sca-1(+) macrophages compared to their counterpart Sca-1(-) macrophages. Depletion of Sca-1(+) macrophages using anti-Sca-1 antibody significantly increased survival rate and reduced lung and kidney damage in an LPS-induced sepsis model. Taken together, we discovered a novel population of Sca-1(+) macrophages in LPS-induced septic conditions. (C) 2020 Elsevier Inc. All rights reserved.