The hyperinflammatory response is one of the main complications associated with novel coronavirus disease 2019 (COVID-19), and there is no effective treatment for cytokine storm. Therefore, it is important to investigate the key genes associated with severity of the disease.In this study, we used a microarray data set to analyze the key genes associated with severe illness in patients with COVID-19. The proportion of immune cells was determined using the CIBERSORT algorithm. The key genes were further verified by detecting the levels of cytokines and chemokines in the serum of patients. Additionally, macrophages were stimulated with SARS-CoV-2 spike protein and chemokine ligand (CCL) 2. The expression of cytokines, ERK1/2, and NF-κB in macrophages was detected.Four hub genes were identified. Among them, C-C motif chemokine receptor 2 (CCR2) was an upregulated hub gene, while killer cell lectin-like receptor subfamily K member 1 (KLRK1), macrophage colony-stimulating factor receptor (CSF1R), and CD3D human recombinant protein (CD3D) were downregulated genes. Immune cell type identification found that the proportion of monocytes was higher in patients with severe COVID-19 than that in controls. Moreover, levels of CCL2 were significantly higher in patients with COVID-19. When stimulated with SARS-CoV-2 S protein and CCL2, macrophages secreted more inflammatory cytokines. The expression level of ERK1/2 was elevated.These results suggested that S protein and CCL2 may mediate macrophage inflammatory responses through the ERK1/2 signaling pathway. This study provides a basis for clinical treatment and improves the prognosis of critically ill patients with COVID-19.