Sca-1 expression depicts pro-inflammatory murine neutrophils under steady state and pathological conditions
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Neutrophils play a crucial role in various pathophysiological conditions, yet targeting them for therapeutic intervention has been discouraged due to the associated risk of infections. Thus, identification of neutrophil subsets and their involvement in inflammatory conditions is warranted for targeted therapeutic strategies. This study, through screening of surface proteins on neutrophils isolated from different tissue microenvironments, identified a distinct neutrophil subset, CD11b + Ly6G + Sca1 + neutrophils, expressing Stem cell antigen-1 (Sca-1). Interestingly, these Sca1 pos neutrophils were more abundant in the liver than BM, blood, and lungs. Further analysis revealed that Sca1pos neutrophils are mature and activated with enhanced effector functions, including superoxide generation, phagocytosis, degranulation, and NETosis. Tracing studies demonstrated ageing-independent characteristics of Sca1 pos neutrophils. Remarkably, Sca1 pos pro-inflammatory neutrophils promote T cell proliferation through ROS, while inhibition of Sca-1 restores T cell proliferation and ROS generation. Intriguingly, inflammatory as well as metabolic cues induce the transition of conventional neutrophils (Sca1 neg ) to Sca1 pos neutrophils and differentiation of progenitors (granulocyte monocyte progenitors, GMPs) into Sca1 pos neutrophils. Furthermore, in vivo models of acute inflammation, peritonitis, and chronic inflammatory condition, non-alcoholic steatohepatitis (NASH), exhibit an increase of Sca1 pos neutrophils at inflammatory sites, while the pharmacological approach using NAC specifically mitigates the expansion of these pro-inflammatory neutrophils. Collectively, our findings unveil a novel subset of Sca1 pos neutrophils with implications for inflammation.
Significance Statement
Neutrophilic inflammation remains the leading driver in infectious and inflammatory diseases. Targeting neutrophil populations remained un-recommended due to hampering the immunological functions of neutrophils. The heterogeneity of neutrophils provides the perspective to target altered neutrophil subsets, but subtle changes defining neutrophil subsets make it complex and ambiguous. Our study identified abundant expression of Sca1on distinct neutrophils under steady state and inflammation. Thus, we reported previously undefined Sca1 pos pro-inflammatory neutrophil subsets and elucidated their regulation. This study further established their involvement in acute and chronic inflammatory conditions. This understanding may further pave the way toward targeting specific neutrophil subsets in pathologies characterized by neutrophilic inflammation.
Graphical Abstract
Highlights
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CD11b + Ly6G + Sca1 + neutrophil subset identified with <1% presence in BM and >40% frequency in the liver.
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These neutrophils are mature and activated, demonstrating enhanced effector functions.
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Sca1 pos neutrophils promote T cell proliferation and display pro-inflammatory characteristics.
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Conventional Sca1 neg neutrophils transition into Sca1 pos neutrophils in response to inflammatory signals, while progenitors undergo differentiation.
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Both acute and chronic inflammatory models show the expansion of CD11b + Ly6G + Sca1 + neutrophils.
