Extracellular CIRP Induces Novel Nectin-2+ (CD112+) Neutrophils to Promote Th1 Differentiation in Sepsis

Abstract

Neutrophil heterogeneity represents different subtypes, states, phenotypes, and functionality of neutrophils implicated in sepsis pathobiology. Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern that promotes inflammation and alters neutrophil phenotype and function through TLR4. Nectin-2 or CD112 is an Ig-like superfamily member. CD112 serves as the ligand for DNAM-1 (CD226), which induces Th1 differentiation in naive CD4+ T cells. Th1 cells produce IFN-γ to fuel inflammation. CD112 is expressed mainly on APCs, but its expression in neutrophils is unknown. We hypothesize that eCIRP induces CD112 expression in neutrophils, promoting Th1 differentiation in sepsis. Incubation of neutrophils with recombinant murine (rm)CIRP significantly increased the gene and protein expression of CD112 in neutrophils. Anti-TLR4 Ab-treated neutrophils significantly decreased CD112+ neutrophils compared with controls upon rmCIRP stimulation. After 4 h of rmCIRP injection in mice, CD112+ neutrophils were significantly increased in the blood and spleen. At 20 h after cecal ligation and puncture–induced sepsis, CD112+ neutrophils were also significantly increased. Blood and splenic CD112+ neutrophils in septic CIRP−/− mice were much lower than in septic wild-type mice. Coculture of naive CD4 T cells with rmCIRP-treated (CD112+) neutrophils significantly increased IFN-γ-producing Th1 cells compared with coculture with PBS-treated neutrophils. CD112 Ab significantly attenuated Th1 differentiation induced by rmCIRP-treated neutrophils. Thus, eCIRP increases CD112 expression in neutrophils via TLR4 to promote Th1 differentiation in sepsis. Targeting eCIRP may attenuate sepsis by reducing Th1-promoting CD112+ neutrophils.

Transcriptomic profiling of immune cells in murine polymicrobial sepsis

“…It is also meaningful to evaluate the molecules and pathways related to cell death simultaneously to grasp the mechanisms of cellular aging from a wider perspective. Our previous studies revealed several novel subtypes of neutrophils, including APANs, nectin-2, and serpin B2 neutrophils, which were found to be upregulated during sepsis (9,10,33). However, our latest scRNA-seq data could not distinctly demonstrate these specific neutrophil subtypes.…”

Histological Characteristics of Experimental Wounds of Soft Tissues of the Femur of Rats and the Role of IFN-γ in the Dynamics of their Healing

“…Наше дослідження показало значне підвищення вмісту IFN-γ через 10 діб після хірургічного моделювання ушкоджень м'яких тканин. Ймовірно, це обумовлено запальними процесами, що продовжувались у глибоких шарах ранового каналу, адже відома здатність цього цитокіну стимулювати активність нейтрофілів і макрофагів [8,11]. Запальна фаза у репаративних процесах має ключове значення для успішного загоєння ушкоджень, завдяки ефективному усуненню інфекційних агентів і залишків некротизованих тканин [12].…”