Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease

Abstract

Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14+ DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14+ mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.

Inflammation and autoimmunity are interrelated in patients with sickle cell disease at a steady-state condition: implications for vaso-occlusive crisis, pain, and sensory sensitivity

“…Sickle-shaped RBCs are more fragile and prone to rupture, leading to the chronic release of hemoglobin and other cellular components. Hemoglobin is a potent pro-inflammatory molecule that activates immune cells such as monocytes, macrophages, and dendritic cells (DCs), prompting them to produce pro-inflammatory cytokines such as IL-1β ( 23 ), IL-6 ( 24 ), and TNF-α ( 23 ). Additionally, heme, an iron-containing component of hemoglobin, can further induce the production of pro-inflammatory cytokines, chemokines, and adhesion molecules by activating NF- κ B and TLR4 signaling pathways, and promote the recruitment of leukocytes and platelets to sites of inflammation, exacerbating the inflammatory response ( 25 ).…”

A Review of the Relationship between the Immune Response, Inflammation, Oxidative Stress, and the Pathogenesis of Sickle Cell Anaemia

“…The innate and adaptive immune responses in SCD are impaired and cannot effectively protect against infection [25,26] with some researchers reporting that the persistent activation of the innate immune system results in the generation of excessive amounts of reactive oxygen species (ROS) (13,(28)(29)(30). According to Ahmad and Ahsan [27], Engwa et al [28] and Atiku et al [10] elevated amounts of reactive species induce oxidative stress and tissue injury, while other reports have revealed that the adaptive immune cells are also dysfunctional, resulting in lower antibody levels compared to healthy individuals [24].…”

“…According to Ahmad and Ahsan [ 27 ], Engwa et al [ 28 ] and Atiku et al [ 10 ] elevated amounts of reactive species induce oxidative stress and tissue injury, while other reports have revealed that the adaptive immune cells are also dysfunctional, resulting in lower antibody levels compared to healthy individuals [ 24 ]. In addition, preliminary studies have revealed that the number of T and B cells, as well as their function, are impaired [ 24 , 26 , 29 ]. Based on these investigations, this review aims to examine the current literature and provide an updated understanding of the relationship between the immune response, inflammation, oxidative stress, blood transfusion, and the pathogenesis of SCD.…”