Table 1.

Representative of Histopathological Changes, Cytokine and Chemokine Secretions, and Cellular Origins in SARS-CoV-2 Infection.

Modulator	Main Cell Source	Type and Function	Clinical Feature		Reference
Cytokines
IL-6	Macrophage, monocyte, activated T cell, dendritic cell, Th2, epithelial cell, endothelium cell, fibroblast	Proinflammatory cytokine; pyrogenic and antibody-enhancing function; induces acute-phase reactants Key player in COVID-19 pathology (neutrophils’ chemotaxis, lymphocytes exhaustion, and lymphocyte necrosis) and its exacerbated inflammatory responses; serum circulation positively correlates with disease severity; negative regulate T cell by increasing the exhaustion markers; main player in cytokine storms	Body	Fever, anemia, vascular leakage, interstitial edema, myocardial dysfunction, cardiomyopathy, complement & coagulation cascade activation, diffused intravascular coagulation; shock, respiratory failure, multiorgan dysfunction	(4, 6, 8, 9, 20, 22–24, 28, 36–39, 58, 65–88)
			Lung	Acute respiratory distress syndrome (ARDS), endothelial dysfunction, thrombin formation, and impaired fibrinolysis
			Kidney	Acute kidney injury
			Liver	Increased acute-phase protein
IL-1β	Macrophage, monocyte, endothelium cell, activated T cell, dendritic cell	Inflammasome-induced cytokine May correlate with inflammation intensity and Th1 cell activation; activates and increases IL-6 production; dysfunction drives macrophage activation syndrome	Body	Fever	(4, 6, 8, 9, 12, 28, 67, 68, 77, 78, 89–92)
			Lung	ARDS
			Liver	Increased acute-phase protein
IL-18	Th1, endothelium cell, fibroblast, activated T cell, macrophage	Proinflammatory cytokine; regulates both Th1 and Th2 responses Associates with type I interferon in COVID-19; serum concentration correlates with increase in pneumonia severity	Lung	ARDS	(8, 12, 68, 93, 94)
			Liver	Liver damage
IL-10	Macrophage, monocyte, Th1 and Th2	Anti-inflammatory cytokine; inhibits Th1 cells and cytokine release Associated with COVID-19 severity; negative regulation of T cells by an increase of exhaustion markers; may expand cytotoxic effector CD8+ T cells, causes hyperactivation of adaptive immunity; high concentrations correlate with low viral load.	Lung	ARDS	(70–72, 77, 79–81, 95–99)
			Liver	Increased acute-phase protein
IL-17	Macrophage, iNKT cell, Th17, neutrophil	Proinflammatory cytokine; neutrophilic inflammation-promoting cytokine Associates with Th17 responses, viral load, severity of disease in COVID-19	Lung	Acute lung injury, ARDS	(37, 79, 98, 100–102)
IFN-γ	Macrophage, Th1 cell, Th17 cell, CD8+ T cell, CD4+ T cell, dendritic cell, NK cell	Proinflammatory cytokine; activates macrophages Impaired activity in severe disease; increased levels strongly correlate with Th1 cell activation	Body	Fever, impaired hematopoietic function, disseminated intravascular coagulation, decreased serum protein, headaches, chills, fatigue, malaise, cardiomyopathy, vascular leakage, production of acute-phase protein.	(4, 9, 12, 28, 36, 68–70, 72, 76, 77, 79, 101, 103–106)
			Lung	ARDS, lung injury
TNF-α	Macrophage, monocyte, Th1, Th17, CD8+ T cell, dendritic cell, epithelial cell, endothelium cell	Pyrogenic cytokine; increases vascular permeability Impaired activity in severe patients with COVID-19; increases IL-6 production; main contributor to cytokine storm interplay; negative regulate T cell by increasing the exhaustion markers	Body	Impaired hematopoietic function, disseminated intravascular coagulation, debilitating, hyperlipidemia, flu-like symptoms	(4, 6, 8, 9, 28, 36, 37, 66, 68–72, 77–80, 86, 91, 98, 101, 105, 106)
			Lung	Alveolar edema, proteinaceous exudates, desquamation of pneumocytes, ARDS
			Liver	Liver damage
Chemokines
CCLX	Macrophage, monocyte, activated T cell, dendritic cell, alveolar epithelial cell	CXCL9, CXCL10, CXCL11, CCL2, CCL3, CCL4, CCL7, CCL8, CCL20, CXCL6, CCL5, and IL-8 are upregulated in COVID-19	Lung	ARDS	(4, 6, 8, 9, 68, 77, 96, 107)
CXCL10	Macrophage, dendritic cell, Th2 cell	Interferon γ-inducible chemokine; recruitment of macrophages, Th1 cells, NK cells Positively correlates with Murray score, viral load, and disease severity; increased levels strongly indicate Th1 cell activation	Lung	ARDS	(9, 68, 70, 71, 77, 79, 91, 98, 108)
IL-8	Macrophage, monocyte, epithelial cell, endothelium cell	Recruits neutrophils Associates with severity of disease in COVID-19	Lung	ARDS	(4, 9, 37, 77, 79, 91, 109)
GM-CSF	Macrophage, monocyte, activated T cell, epithelial cell	Proinflammatory cytokine, stimulating proinflammatory cytokines and chemokines Associated with Th17 responses; GM-CSF secretion of immune cells (CD4+ T cells, CD8+ T cells, NK cells, and B cells) significantly higher	Lung	ARDS	(4, 6, 9, 36, 70, 77–79, 96, 110–112)
			Liver	Increased acute-phase protein