Figure 2.

Red blood cells and their derivatives regulate immune responses in sepsis. (a) red blood cells in the bloodstream, through their negatively charged membrane, attract the pathogens and engulf them. Toll-like receptor-9 recognizes the pathogen's mitochondrial DNA (mtDNA), leading to activation of inflammasomes to inhibit pro-inflammatory stimuli and suppress inflammation. (b) Red blood cells, through mitogenic stimulation, enhance mouse spleen cells and mononuclear cells to secrete Colony-stimulating factors (CSFs) and cytokines, such as interleukin-2 to increase T-cell proliferation. Under conditions without mitogenic stimulation, red blood cells directly increase interleukin-2 receptor expression, which results in T-cell proliferation through nonspecific interactions with the CD2 antigen on T cells. (c) During eryptosis, red blood cells release exosomes through budding, which, through APCs, modulate mitogens leading to CD4+/CD8+ T-cell proliferation. (d) During hemolysis, when red blood cells lyse hemoglobin, hemoglobin is degraded to heme through binding of the CD163 antigen, leading to macrophage-induced heme oxygenase 1 expression, resulting in heme metabolism to biliverdin, ferritin, and carbon monoxide, which then inhibits oxidative damage. (e) Hemoglobin and heme, through pathogen-associated molecular patterns (PAMPs), produce reactive oxygen species against pathogen infection, while heme decreases the production of nitric oxide to inhibit septic shock. (f) Hemoglobin is degraded by macrophage cathepsin D or neutrophil cathepsin G to the opioid peptide hemorphin, such as VV-hemorphin-7 or LVV-hemorphin 7. Studies have shown their anti-inflammatory effects, but not the exact pathway