Temperature as a Regulator of Red Blood Cell Fate: From Membrane Dynamics to Cellular Clearance

Fever-range hyperthermia (38-41 °C) is a typical physiological response to infection, inflammation, and systemic stress. Although increased temperatures are known to affect blood rheology and erythrocyte activity, their comprehensive impact on red blood cell (RBC) structure, mechanics, and lifespan remains incompletely understood. This review summarizes current understanding of how moderate hyperthermia affects RBC membrane structure, internal behavior, mechanical properties, and clearance cues. Evidence shows that brief exposure to febrile temperatures primarily induces reversible biophysical modifications, including heightened membrane fluidity, increased membrane fluctuations, changes in hemoglobin-water interactions, and short-term improvements in deformability. These changes reflect adaptive adjustments within the membrane-cytosol-cytoskeleton system, potentially temporarily boosting microcirculatory flow. On the other hand, prolonged or repeated heat stress causes oxidative damage, hemoglobin auto-oxidation, accumulation of membrane-bound hemoglobin, band 3 clustering, cytoskeletal restructuring, calcium imbalance, and disruption of membrane lipid asymmetry. These effects weaken membrane stability and lead to vesiculation, shape changes, increased cell fragility, altered aggregation, enhanced adhesion, and activation of clearance mechanisms. A primary focus is the transition from reversible membrane softening to permanent structural damage over time. The research supports a model in which temperature affects RBC mechanics and related membrane, cytosolic, and signaling processes that influence RBC viability. We propose interpreting febrile hyperthermia as a dynamic factor that shifts RBCs from an adaptive phase to accelerated aging and removal during prolonged heat exposure. This perspective enhances our understanding of RBC behavior during fever and systemic inflammation and underscores the role of temperature in shaping erythrocyte function and lifespan.