Metabolic Influences Modulating Erythrocyte Deformability and Eryptosis

Abstract

Many factors in the surrounding environment have been reported to influence erythrocyte deformability. It is likely that some influences represent reversible changes in erythrocyte rigidity that may be involved in physiological regulation, while others represent the early stages of eryptosis, i.e., the red cell self-programmed death. For example, erythrocyte rigidification during exercise is probably a reversible physiological mechanism, while the alterations of red blood cells (RBCs) observed in pathological conditions (inflammation, type 2 diabetes, and sickle-cell disease) are more likely to lead to eryptosis. The splenic clearance of rigid erythrocytes is the major regulator of RBC deformability. The physicochemical characteristics of the surrounding environment (thermal injury, pH, osmolality, oxidative stress, and plasma protein profile) also play a major role. However, there are many other factors that influence RBC deformability and eryptosis. In this comprehensive review, we discuss the various elements and circulating molecules that might influence RBCs and modify their deformability: purinergic signaling, gasotransmitters such as nitric oxide (NO), divalent cations (magnesium, zinc, and Fe²⁺), lactate, ketone bodies, blood lipids, and several circulating hormones. Meal composition (caloric and carbohydrate intake) also modifies RBC deformability. Therefore, RBC deformability appears to be under the influence of many factors. This suggests that several homeostatic regulatory loops adapt the red cell rigidity to the physiological conditions in order to cope with the need for oxygen or fuel delivery to tissues. Furthermore, many conditions appear to irreversibly damage red cells, resulting in their destruction and removal from the blood. These two categories of modifications to erythrocyte deformability should thus be differentiated.

Keywords: COVID-19; eryptosis; erythrocyte deformability; homeostasis; hormones; metabolism; sleep apnea; stress.

Figure 1

A brief overview of eryptosis (adapted from [47]) showing the pathways that initiate it, under the influence of osmotic shock or oxidative stress, resulting in activation of intracellular pathways, leading in turn to phospholipid membrane scrambling (1); cell shrinkage (2); and membrane blebbing (3). Figure created using www.biorender.com accessed on 17 December 2021.

Figure 2

Morphology of RBCs in the presence of high circulating serum ferritin. This picture shows that in conditions like hemochromatosis, RBC structure is markedly compromised. (A) Individual with hereditary hemochromatosis (H63D/C2882Y), serum ferritin level 374 ng/mL⁻¹; (B) individual with hereditary hemochromatosis (H63D/wild type), serum ferritin level 1500 ng/mL⁻¹. Raw data from [72].

Figure 3

A representative RBC from a type 2 diabetes patient (Raw data from [83]. Erythrocyte deformability is often found to be moderately impaired in diabetes mellitus patients, due to several metabolic and hormonal disturbances (glycation and oxidative stress) that may also promote eryptosis. This is an example of “covertly abnormal blood rheology”, which is supposed to induce microcirculatory disturbances. The main glucose-regulating hormones insulin and glucagon have also been reported to exert an influence on red cell deformability, whose pathophysiological relevance remains unclear.

Figure 4

Regulatory loops involved in the modulation of red cell deformability. According to the physiological or pathological context, the factors thoroughly enumerated in this review increase or decrease red cell deformability, thus contributing to the adaptation of microcirculatory blood flow to this context. Erythrocyte stiffening may be a reversible event or one of the components of the cascade of events leading to programmed red cell death (eryptosis). Figure created using www.biorender.com accessed on 17 December 2021.