DOI: 10.1097/shk.0000000000002919 ISSN: 1540-0514

IL1R2⁺ Inflammatory Monocytes Contribute to Immune Dysregulation and Predict Mortality in COVID-19

Yiying Yang, Fang Yu, Muyuan Li, Hao Ma, Huali Zhang, Xianzhong Xiao, Liqin Cheng
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Background:

Coronavirus disease 2019 (COVID-19) is characterized by dysregulated immune responses and excessive inflammation, contributing to severe disease and mortality. Interleukin-1 receptor type 2 (IL1R2), a decoy receptor for interleukin-1 (IL-1), regulates inflammatory responses; however, its cellular distribution and clinical significance in COVID-19 remain unclear.

Methods:

Publicly available single-cell RNA sequencing (scRNA-seq) dataset (GSE149689) of peripheral blood mononuclear cells (PBMCs) from COVID-19 patients were analyzed. An independent monocyte transcriptomic dataset (GSE198256) was analyzed to evaluate IL1R2 dynamics during COVID-19 and recovery. Differential expression, functional enrichment, regulon activity, and CellChat analyses were performed to characterize IL1R2 ⁺ monocytes. Serum IL1R2 levels were measured in COVID-19 patients and healthy controls (HCs), and their associations with disease severity and mortality were evaluated.

Results:

Single-cell analysis revealed that IL1R2 was predominantly expressed in monocytes from COVID-19 patients. IL1R2 expression was increased during active COVID-19 and decreased after recovery. IL1R2 ⁺ monocytes exhibited enhanced inflammatory transcriptional programs, increased activity of inflammation-associated regulons, and activation of TNFα/NF-κB, interferon, and IL6-JAK-STAT3 pathways. Cell–cell communication analysis identified IL1R2 ⁺ monocytes as active mediators of CCL, CXCL, IL1, and TNF signaling networks. Serum IL1R2 levels were elevated in COVID-19 patients, further increased in non-survivors, and correlated with inflammatory markers, tissue injury indicators, and coagulation abnormalities. IL1R2 showed predictive performance for mortality comparable to procalcitonin and D-dimer.

Conclusions:

IL1R2 identifies a highly inflammatory monocyte state associated with COVID-19 immune dysregulation. Elevated IL1R2 levels reflect disease activity and poor outcomes, supporting its potential role as a complementary prognostic biomarker and therapeutic target.

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