When blood needs to flow: The role of the complement system in red blood cell clearance during immune responses

The complement system is a crucial component of the innate immune response, primarily recognized for its defensive role against pathogens. Increased red blood cell (RBC) mortality due to complement activation during infections is often considered collateral damage of this defensive role. In this study, we propose that this phenomenon results from the active regulation of RBC mortality by the complement system during acute immune responses. Traditionally, RBC homeostasis has been explained by the need to ensure adequate oxygen delivery. However, RBCs are also critical determinants of blood viscosity, which directly influences tissue perfusion. Efficient immune responses require increased blood flow to infected tissues, but changes in plasma proteins during acute-phase responses can increase blood viscosity, hindering perfusion. We suggest that the complement system selectively removes less elastic RBCs, compensating for the rise in plasma viscosity and optimizing tissue perfusion during infections. Our findings reveal a previously unrecognized role of the complement system in regulating blood flow, highlighting the intricate balance between complement’s homeostatic and defensive functions in maintaining physiological stability.