bims-sicedi Biomed News
on Sickle cell disease
Issue of 2026–01–04
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Fetal Hemoglobin Research and Clinical Relevance in Sickle Cell Disease.
  2. A case of SCD controlled by IMiDs and hydroxyurea.
  3. Suspension physics govern the multiscale dynamics of blood flow in sickle cell disease.
  4. Heme-Induced Activation of the TLR3/TRIF-IFN-I-CCL2 Pathway Contributes to Kidney Injury in Sickle Cell Disease.
  5. Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease.
  6. Proteomic Analysis of Golden Sputum Reveals Pulmonary Complement Activation During Acute Chest Syndrome in Children With Sickle Cell Disease.
  7. Hydroxycarbamide and Sickle Cell Anemia: Paradoxical Effects Related to Redox Mechanisms of Cellular Adaptation.
  8. Iron, Oxidative Stress, and Haptoglobin Gene Polymorphism in Sickle Cell Disease Patients With Inflammation in Cameroon: An Analytical Cross-Sectional Study.
  1. Physiology (Bethesda). 2025 Dec 30.
    Fetal Hemoglobin Research and Clinical Relevance in Sickle Cell Disease.
    Bjorg Gudmundsdottir, John F Tisdale.
      Sickle cell disease (SCD) is the most common monogenic disorder, globally affecting close to eight million individuals. SCD is a devastating disease where patients suffer from extreme pain due to vaso-occlusive episodes (VOEs), end-organ damage and premature death. The burden of SCD is projected to rise significantly in the near future, making basic and clinical research to develop curative treatments even more acute. SCD was the first genetic disorder where the underlying molecular alterations were defined, an amino acid change resulting in polymerization of the sickle hemoglobin molecule and blockage of capillary vessels. One of the major findings in the field is the realization that fetal hemoglobin (HbF) expression, which is turned off shortly after birth in majority of people, can ameliorate the symptoms of SCD when it persists. Therefore, conceiving a strategy to reactivate expression of HbF in adult erythroid cells became a viable therapeutic option. In this review we provide a historical overview of the key discoveries of fetal and sickle hemoglobin research and the major clinical applications that were implemented based on those findings, including Hydroxyurea, to lessen symptoms by increasing HbF levels. We also discuss other therapeutic opportunities to treat symptoms or cure SCD.
    Keywords:  Fetal hemoglobin; Gene therapy; Sickle Cell Disease; Transplantation
    DOI:  https://doi.org/10.1152/physiol.00024.2025
  2. Int J Hematol. 2025 Dec 27.
    A case of SCD controlled by IMiDs and hydroxyurea.
    Ashrei Bayewitz, Sai Shalini Pillarisetty, Fatemeh Moeini Nia.
      IMiDs (immunomodulatory drugs from the thalidomide class) enhance hemoglobin F (HbF) production but are not yet approved for sickle cell disease (SCD). Here, we describe a case of severe SCD and multiple myeloma (MM) in which over 6 years of treatment with IMiDs and hydroxyurea led to sustained remission of SCD.
    Keywords:  Fetal hemoglobin (HbF); Hydroxyurea; Multiple myeloma (MM); Pomalidomide; Sickle cell disease (SCD)
    DOI:  https://doi.org/10.1007/s12185-025-04146-2
  3. Sci Adv. 2026 Jan 02. 12(1): eadx3842
    Suspension physics govern the multiscale dynamics of blood flow in sickle cell disease.
    Hannah M Szafraniec, Freya Bull, John M Higgins, Howard A Stone, Timm Krüger, Philip Pearce, David K Wood.
      From diabetes to malaria, altered blood flow contributes to poor clinical outcomes. Heterogeneity in red blood cell (RBC) properties within and across individuals has hindered our ability to establish the multiscale mechanisms driving pathological flow dynamics in such diseases. To address this, we develop microfluidic platforms to measure RBC properties and flow dynamics in the same blood samples from patients with sickle cell disease (SCD). We find that effective blood viscosity across individuals is explained by the proportion of stiff RBCs, exhibiting qualitative similarities to rigid-particle suspensions, despite considerable mechanical heterogeneity. By combining simulations with spatially resolved measurements of cell dynamics, we show how features of emergent rheology are governed by spatiotemporal cell organization, via margination at intermediate oxygen tensions, and localized jamming caused by spatial hematocrit variations under hypoxia. Our work defines the suspension physics underlying pathological blood flow in SCD and, more broadly, emergent rheology in heterogeneous particle suspensions.
    DOI:  https://doi.org/10.1126/sciadv.adx3842
  4. Blood. 2026 Jan 02. pii: blood.2025031060. [Epub ahead of print]
    Heme-Induced Activation of the TLR3/TRIF-IFN-I-CCL2 Pathway Contributes to Kidney Injury in Sickle Cell Disease.
    Yunfeng Liu, Sarah Shayo, Shan Su, Weili Bao, Hui Zhong, Irina Murakhovskaya, Cheryl A Lobo, Xiuli An, Deepa G Manwani, Patricia A Shi, Karina Yazdanbakhsh.
      Sickle cell nephropathy (SCN) is a major clinical complication in sickle cell disease (SCD), yet its underlying mechanisms remain incompletely defined. Hemolysis, a hallmark of SCD, has been implicated in SCN pathogenesis, but the downstream inflammatory pathways are not fully understood. We previously demonstrated that hemolysis triggers type I interferon (IFN-I) responses, leading to upregulation of the chemokine CCL2 and recruitment of classical monocytes that differentiate into monocyte-derived macrophages (MoMϕ) within livers in SCD. In this study, we show that IFN-I and CCL2 levels are elevated in the plasma of SCD patients with abnormal urine albumin-creatinine ratio (uACR) and in the kidneys of Townes SCD mouse model. Using IFN-I receptor (Ifnar1)-/- and CCL2 receptor (Ccr2)-/- mouse models of SCD, we demonstrate that loss of IFN-I or CCL2 signaling reduces MoMϕ accumulation, renal inflammation, and renal injury. Mechanistically, we identify that hemin-induced IFN-I production occurs via the TLR3/TRIF signaling axis, independent of MyD88, MAVS, or STING. These findings uncover a previously unrecognized heme-TLR3/TRIF-IFN-I-CCL2 pathway that contributes to renal pathology in SCD and suggest that targeting this axis may offer therapeutic benefit.
    DOI:  https://doi.org/10.1182/blood.2025031060
  5. Exp Hematol. 2025 Dec 31. pii: S0301-472X(25)00645-9. [Epub ahead of print] 105366
    Anti-IL-18 immunotherapy decreases inflammatory and vaso-occlusive responses in mice with sickle cell disease.
    Érica M F Gotardo, Lidiane S Torres, Irmgard Förster, Lucas F S Gushiken, Pâmela L Brito, Flavia C Leonardo, Bruna Cunha Zaidan, Andreas Bruederle, Sergei Agoulnik, Jiri Kovarik, John Millholland, Fernando F Costa, Nicola Conran.
       BACKGROUND: Sickle cell disease (SCD) is characterized by inflammatory and vaso-occlusive processes that drive acute crises and progressive organ damage. Interleukin-18 (IL-18), elevated in SCD patients and mouse models, contributes to these pathological mechanisms.
    METHODS: We evaluated the effects of acute and prolonged IL-18 blockade using the SK113AE-4 monoclonal antibody in Townes and Berkeley SCD mice.
    RESULTS: Acute IL-18 neutralization reduced TNF-α-induced microvascular leukocyte recruitment and prevented hypoperfusion, indicating that modulation of inflammatory signaling improves physiological responses in SCD. Prolonged anti-IL-18 immunotherapy for 6 weeks decreased circulating TNF-α and IL-10 and reduced hepatic macrophage infiltration, but did not prevent liver fibrosis, iron deposition, or alter biochemical markers of hemolysis or hepatic/renal injury. As such, IL-18 blockade attenuates vascular inflammation and vaso-occlusive-like events, but may be insufficient to prevent SCD-related liver injury under the conditions tested. In contrast, in our previous study, anti-IL-1β immunotherapy provided added liver protection, highlighting potentially divergent cytokine pathways in SCD.
    CONCLUSIONS: Collectively, these results support IL-18 as a therapeutic target to reduce vascular inflammation and vaso-occlusive processes, and suggest that combined inflammasome cytokine-targeted or multi-approach strategies may be required to prevent organ damage in SCD.
    TEASER ABSTRACT: IL-18 is elevated in sickle cell disease (SCD) and contributes to inflammatory and vaso-occlusive pathways. Using two SCD mouse models, we show that acute IL-18 blockade improves microvascular responses and preserves skin perfusion after TNF-α challenge. Prolonged IL-18 inhibition reduces some inflammatory markers but does not prevent liver injury. These findings support IL-18 as a target to limit vascular inflammation in SCD, while indicating that preventing organ damage may require broader or combined approaches.
    Keywords:  Cytokine; Inflammasome; inflammation; liver; sickle cell disease; vaso-occlusion
    DOI:  https://doi.org/10.1016/j.exphem.2025.105366
  6. Am J Hematol. 2025 Dec 30.
    Proteomic Analysis of Golden Sputum Reveals Pulmonary Complement Activation During Acute Chest Syndrome in Children With Sickle Cell Disease.
    Slimane Allali, Nabiha Sbeih, Rachel Rignault-Bricard, Johanna Bruce, Morgane Le Gall, Claire Heilbronner, Noemie de Cacqueray, Sofia Angyalosy, Melissa Taylor, Joséphine Brice, Mariane de Montalembert, Martina Bevacqua, Emilie-Fleur Gautier, Olivier Hermine, Thiago Trovati Maciel.
      Acute chest syndrome (ACS) is one of the most common severe complications of sickle cell disease (SCD). In recent years, a major role of inflammation and innate immunity has been evidenced, but ACS pathophysiology remains incompletely understood, and therapeutic options are limited. We performed proteomic analysis of induced sputum and tracheal aspirates in eight SCD children during ACS (four intubated and four non-intubated) and in three during vaso-occlusive crisis (VOC) without ACS. Proteomic analysis revealed that one of the main canonical pathways involved during ACS was the complement system. To further investigate its implication, we measured the main components of the complement alternative and terminal pathways in sputum and plasma from SCD children during 27 ACS episodes compared with 16 VOC episodes without ACS. A dramatic increase in the median level of C3a, C5a, sC5b-9, factor B, factor D, properdin, and factor H was observed in the sputum from SCD children during ACS. In the plasma, no significant increase was observed during ACS compared to VOC, except for sC5b-9, whose median level was twofold higher than during VOC but 16-fold lower than the sC5b-9 median level in the sputum during ACS. Also, the C3a/C3 and C5a/C5 ratios were significantly increased in sputum compared to plasma during ACS, reflecting a predominant local pulmonary activation of the complement system compared to systemic activation. Our results reveal the potentially crucial role of complement activation in the lungs during ACS and open new therapeutic perspectives with anti-complement agents for this severe complication of SCD.
    Keywords:  acute chest syndrome; child; complement activation; sickle cell disease; sputum
    DOI:  https://doi.org/10.1002/ajh.70182
  7. ACS Omega. 2025 Dec 23. 10(50): 61701-61709
    Hydroxycarbamide and Sickle Cell Anemia: Paradoxical Effects Related to Redox Mechanisms of Cellular Adaptation.
    Ilana Luize Rocha Santana, Victoria Simões Bernardo, Edis Belini Junior, Pâmela Lourdes Pereira da Silva, Danilo Grünig Humberto da Silva, Larissa Paola Rodrigues Venancio.
      Sickle cell anemia (SCA) is a hemolytic anemia characterized by a chronic redox imbalance with few disease-modifying treatments available. In this study, we aimed to determine the influence of hydroxycarbamide (HC) treatment on the redox mechanisms of cellular adaptation in patients with SCA. We analyzed 10 patients treated (HC+) and 9 not treated (HC-). We evaluated, by RT-qPCR, the transcript levels of the transcription factors NRF2 and ATF4, their modulators (KEAP1, AKT, and PI3K), and the antioxidants (SOD1, CAT, PRDX1, and GPX1). We also collected data on biochemical parameters, including total leukocyte count, direct and indirect bilirubin, lactic acid dehydrogenase (LDH), and fetal hemoglobin (HbF%) levels, by analyzing the participants' medical records. Among the results obtained, NRF2 and AKT presented increased mRNA levels in the HC+ group, but reduced ATF4, CAT, and SOD1 mRNA levels. Multivariate statistical analysis ranked NRF2 and ATF4 as the markers that most characterized the groups studied. Therefore, taking together our results and the literature, we suggest that HC use results in a dynamic relationship between the redox signaling pathways of the investigated transcription factors triggered as part of an adaptive response to this medication, associated with their involvement in Hb F production.
    DOI:  https://doi.org/10.1021/acsomega.5c07897
  8. Biochem Res Int. 2025 ;2025 5303373
    Iron, Oxidative Stress, and Haptoglobin Gene Polymorphism in Sickle Cell Disease Patients With Inflammation in Cameroon: An Analytical Cross-Sectional Study.
    Romaric Tuono De Manfouo, Josué Simo Louokdom, Jean Paul Chedjou, Prosper Cabral Biapa Nya, Wilfried Mbatcham, Claude Tayou Tagny, Constant Anatole Pieme.
       Background and Aims: The more severe forms of sickle cell disease (SCD) are highly inflammatory genetic disorders that cause significant oxidative stress. To fight against the free radicals produced, the body has an antioxidant system. In addition, haptoglobin has been reported in several studies as possessing oxidant and inflammatory properties depending on the nature of the genotype. This study hypothesizes that the HP2 allele of haptoglobin may exacerbate oxidative stress in sickle cell patients with inflammation.
    Methods: An analytical cross-sectional study was conducted for 6 months. The patients recruited were those with severe forms of sickle cell anemia, regularly followed at the hematology department of the Yaoundé Central Hospital and the Bafoussam Regional Hospital. The Public Health Research Biotechnology Laboratory (LAPHER-Biotech) in Yaoundé provided a framework for genotyping haptoglobin by allele-specific PCR. Next, iron, oxidative stress, and inflammatory parameters were assessed by standard methods, and the statistical software R Version 4.1.1. allowed for the data analysis.
    Results: Samples from 149 participants were analyzed. Patients with Hp phenotypes 2-2 had a considerable elevation of reduced glutathione (14.3 μmol/L) compared to those of phenotype Hp 2-1 (11.2 μmol/L) and genotype Hp 1-1 (11.8 μmol/L) (p = 0.075). Malondialdehyde was significantly higher in patients with Hp phenotypes 2-2 compared to those with Hp phenotype 2-1 and Hp phenotype 1-1 (p = 0.008). The oxidative stress index (OSI) was higher in patients with the Hp 2-2 phenotype than those with the Hp 2-1 and Hp 1-1 phenotypes (p = 0.008) suggesting that they are more affected by oxidative stress.
    Conclusion: This study supports the hypothesis that the Hp 2-2 phenotype of haptoglobin is associated with an imbalance in the oxidative balance in favor of oxidants, suggesting that the latter is a major contributor to the worsening pathophysiology of SCD.
    Keywords:  haptoglobin gene polymorphism; oxidative stress; serum iron; sickle cell disease
    DOI:  https://doi.org/10.1155/bri/5303373
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