Antigen-presenting aged neutrophils induce [CD4.sup.+] T cells to exacerbate inflammation in sepsis

• Published in: The Journal of clinical investigation Vol. 133; no. 14
• Main Authors: Jin, Hui, Aziz, Monowar, Murao, Atsushi, Kobritz, Molly, Shih, Andrew J, Adelson, Robert P, Brenner, Max, Wang, Ping
• Format: Journal Article
• Language: English
• Published: American Society for Clinical Investigation 01.07.2023
• Subjects: Antigen presenting cells; Binding proteins; Care and treatment; Development and progression; Gene expression; Genetic aspects; Health aspects; Sepsis; United States
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI164585

Extracellular cold-inducible RNA-binding protein (eCIRP) is a key mediator of severity and mortality in sepsis. We found that stimulation of mouse bone marrow-derived neutrophils (BMDNs) with eCIRP generated a distinct neutrophil subpopulation, characterized by cell surface markers of both antigen-presenting cells and aged neutrophils as well as expression of IL- 12, which we named antigen-presenting aged neutrophils (APANs). The frequency of APANs was significantly increased in the blood, spleen, and lungs of WT mice subjected to cecal ligation and puncture-induced sepsis but not in [CIRP.sup.-/- ] mice. Patients with sepsis had a significant increase in circulating APAN counts compared with healthy individuals. Compared with non-APAN-transfered mice, APAN-transferred septic mice had increased serum levels of injury and inflammatory markers, exacerbated acute lung injury (ALI), and worsened survival. APANs and [CD4.sup.+] T cells colocalized in the spleen, suggesting an immune interaction between these cells. APANs cocultured with [CD4.sup.+] T cells significantly induced the release of IFN-[gamma] via IL-12. BMDNs stimulated with eCIRP and IFN-[gamma] underwent hyper-NETosis. Stimulating human peripheral blood neutrophils with eCIRP also induced APANs, and stimulating human neutrophils with eCIRP and IFN-[gamma] caused hyper-NETosis. Thus, eCIRP released during sepsis induced APANs to aggravate ALI and worsen the survival of septic animals via [CD4.sup.+] T cell activation, Th1 polarization, and IFN-[gamma]-mediated hyper-NETosis.