Antigen-presenting aged neutrophils induce CD4+ T cells to exacerbate inflammation in sepsis

Jin, Hui; Aziz, Monowar; Murao, Atsushi; Kobritz, Molly; Shih, Andrew; Adelson, Robert P.; Wang, Haichao

doi:10.1172/jci164585

Cited by 7 publications

(8 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

Section: B Acontrasting

confidence: 58%

“…eCIRP, the major DAMP in sepsis, inhibited neutrophil apoptosis to induce aged neutrophils (10). Neutrophils possessing both aged and antigen-presenting properties induced Th1 differentiation to aggravate acute lung injury and worsen survival in sepsis (9). Moreover, this novel neutrophil subset was also identified in septic patients (9).…”

Section: B Amentioning

confidence: 97%

“…Neutrophils possessing both aged and antigen-presenting properties induced Th1 differentiation to aggravate acute lung injury and worsen survival in sepsis (9). Moreover, this novel neutrophil subset was also identified in septic patients (9). In addition to neutrophils, however, cellular aging has not been studied extensively in most of other immune cell types such as macrophages and lymphocytes especially in sepsis.…”

Section: B Amentioning

confidence: 99%

“…Our study implies the need for investigating cellular aging in different populations to better understand sepsis pathophysiology. Cellular aging can occur in response to cellular stress or damage irrespective of animals' age (9,10). Mice used in our study were in the same age for each group; thus, the difference in cellular aging status was unlikely to be due to the age of the animals.…”

Section: B Amentioning

confidence: 99%

“…Those subsets exhibit a distinct phenotype reflected by genomic differences even within the same cell population (8). For instance, neutrophils, which were traditionally thought as a terminally differentiated single population, are now known to consist of many subsets, such as aged, antigen-presenting, intercellular adhesion molecule-1 (ICAM-1)-expressing, and lowdensity neutrophils and antigen-presenting aged neutrophils (APANs) in sepsis (9)(10)(11)(12)(13). T-cell and macrophage polarization is no longer highlighted as a simple Th1/Th2 and M1/M2 dichotomy as once thought (8).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Transcriptomic profiling of immune cells in murine polymicrobial sepsis

Murao,

Jha,

Aziz

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

IntroductionVarious immune cell types play critical roles in sepsis with numerous distinct subsets exhibiting unique phenotypes even within the same cell population. Single-cell RNA sequencing (scRNA-seq) enables comprehensive transcriptome profiling and unbiased cell classification. In this study, we have unveiled the transcriptomic landscape of immune cells in sepsis through scRNA-seq analysis.MethodsWe induced sepsis in mice by cecal ligation and puncture. 20 h after the surgery, the spleen and peritoneal lavage were collected. Single-cell suspensions were processed using a 10× Genomics pipeline and sequenced on an Illumina platform. Count matrices were generated using the Cell Ranger pipeline, which maps reads to the mouse reference transcriptome, GRCm38/mm10. Subsequent scRNA-seq analysis was performed using the R package Seurat.ResultsAfter quality control, we subjected the entire data set to unsupervised classification. Four major clusters were identified as neutrophils, macrophages, B cells, and T cells according to their putative markers. Based on the differentially expressed genes, we identified activated pathways in sepsis for each cell type. In neutrophils, pathways related to inflammatory signaling, such as NF-κB and responses to pathogen-associated molecular patterns (PAMPs), cytokines, and hypoxia were activated. In macrophages, activated pathways were the ones related to cell aging, inflammatory signaling, and responses to PAMPs. In B cells, pathways related to endoplasmic reticulum stress were activated. In T cells, activated pathways were the ones related to inflammatory signaling, responses to PAMPs, and acute lung injury. Next, we further classified each cell type into subsets. Neutrophils consisted of four clusters. Some subsets were activated in inflammatory signaling or cell metabolism, whereas others possessed immunoregulatory or aging properties. Macrophages consisted of four clusters, namely, the ones with enhanced aging, lymphocyte activation, extracellular matrix organization, or cytokine activity. B cells consisted of four clusters, including the ones possessing the phenotype of cell maturation or aging. T cells consisted of six clusters, whose phenotypes include molecular translocation or cell activation.ConclusionsTranscriptomic analysis by scRNA-seq has unveiled a comprehensive spectrum of immune cell responses and distinct subsets in the context of sepsis. These findings are poised to enhance our understanding of sepsis pathophysiology, offering avenues for targeting novel molecules, cells, and pathways to combat infectious diseases.

show abstract

Section: B Acontrasting

confidence: 58%

Section: B Amentioning

confidence: 97%