Inflammatory targets of therapy in sickle cell disease

Abstract

Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion, and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident for more than several decades that a more complex disease process contributes to the myriad of clinical complications seen in patients with SCD with inflammation playing a central role. Drugs targeting specific inflammatory pathways therefore offer an attractive therapeutic strategy to ameliorate many of the clinical events in SCD. In addition, they are useful tools to dissect the molecular and cellular mechanisms that promote individual clinical events and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only Food and Drug Administration-approved drug for SCD.

Figure 1. The Inflammasome

NLRP3 senses PAMP and DAMP molecules leading to the recruitment of ASC and inflammasome assembly. The inflammasome mediates caspase cleavage, which facilitates the cleavage and activation of IL-18 and IL-1b which promote inflammation. Several druggable targets in this pathway have been established and have proven efficacious in an array of inflammatory diseases.

Figure 2. The NFκB Pathway

Cytokine signaling and activation of TNFR and TLR is propagated through adaptor molecules such as TRADD, TRAFF, IRAK and MyD88 leading to phosphorylation and activation of the IKK kinase complex. The IKK complex phosphorylates the NFκB Inhibitory protein IκB which promotes polyubiquitination and proteasomal degradation. NFκB will subsequently translocate to the nucleus and bind its DNA response elements known as κB sites, thus leading to mRNA expression of target genes. Anti-Inflammatory therapeutic interventions in SCD that inhibit the phosphorylation of IκB have proven efficacious at inhibiting NFκB activation. (TRAFF, TNF receptor-associated factor 1; TRADD, Tumor necrosis factor receptor type 1-associated DEATH domain protein; IRAK, Interleukin-1 receptor-associated kinase 1; MyD88, Myeloid differentiation primary response protein).

Figure 3. Mast cell activation

Mast cells (M) require the trans-membrane tyrosine kinase receptor C-kit (c-kit) to function properly. Activation of mast cells occurs through binding of ligand to the Fc epsilon R 1 receptor (FcεR1) or independent of it. Activated or de-granulating mast cells (DM) release pro-inflammatory mediators (IM), which attract cells of the innate immune system such as eosinophils (E) or neutrophils (N). Tryptase (T) released from DM excites nociceptors (NOC) on neurons (NEU) to produce the neuropeptides Substance P (SP) and calcitonin gene related peptide (CGRP) whose effect on the endothelial cells (EN) of blood vessels (V) is increased vascular permeability and inflammation. SP causes further mast cell activation and degranulation.