https://orcid.org/0000-0002-9187-4146
In this issue of Blood Advances, Grunenwald et al1 have identified hydroxycarboxylic acid receptor 2 (HCAR2), a G-protein–coupled receptor (GPCR), as a novel receptor for cell-free heme in the context of sickle cell disease (SCD), thereby revealing a new axis of heme sensing with anti-inflammatory potential. Their study adds an important layer to our understanding of how the body regulates the toxic and inflammatory effects of heme that is released during intravascular hemolysis.
SCD, a monogenic disorder, is caused by a mutation in the β-globin gene, which leads to the production of red blood cells that are prone to hemolysis and thus the release of free hemoglobin and heme. Cell-free heme is a potent damage-associated molecular pattern (DAMP) that triggers oxidative stress, systemic inflammation, vascular dysfunction, and tissue injury through Toll-like receptor 4 (TLR4), reactive oxygen species, and nitric oxide depletion.2 GPCRs represent a large and diverse family of signaling molecules that are involved in nearly all physiological processes. Previous studies suggested that heme might engage a GPCR, but the receptor identity remained elusive.3 Grunenwald et al employed bulk RNA sequencing from liver tissue of mouse models of SCD and chemically induced hemolysis to identify common signaling pathways. GPCR signaling, and specifically HCAR2, emerged as significantly enriched in both models. In a broad screen of 241 GPCRs, HCAR2 uniquely responded to heme exposure in a β-arrestin–based reporter assay. Follow-up binding studies using surface plasmon resonance and absorbance spectroscopy confirmed a direct, dose-dependent interaction between heme and HCAR2. Importantly, this interaction was not seen with related receptors, such as GPR109B, suggesting specificity.
The authors then examined the physiological regulation of HCAR2. They found that heme not only acts as a ligand for HCAR2 but also induces its expression in mouse liver and kidney. This upregulation mirrored that of heme oxygenase-1 (HO-1), the key enzyme responsible for heme degradation. Pharmacologic inhibition of HO-1 further increased HCAR2 expression in vivo, pointing to a feedback mechanism in which heme drives HCAR2 and HO-1 expression as a self-limiting response to oxidative stress.
This finding is particularly intriguing given heme’s well-established dual role in inflammation. On one hand, heme is a potent proinflammatory mediator. Activation of TLR4 by heme triggers the production of proinflammatory cytokines, promotes immune cell activation, and induces cell death mechanisms, such as apoptosis and necroptosis.4,5 This pathway has been implicated in the pathogenesis of acute lung injury, vaso-occlusion, and end-organ damage in the liver and kidney in SCD.6
In contrast, heme also induces protective responses. The classical mechanism is through the activation of nuclear factor erythroid 2–related factor 2, a transcription factor that promotes antioxidant gene expression, including HO-1. The HO-1 pathway degrades heme into biliverdin, iron, and carbon monoxide, which have anti-inflammatory and cytoprotective functions against hemolysis.7 The interplay between HCAR2 and HO-1 observed by Grunenwald et al places HCAR2 within this regulatory network.
What makes this discovery particularly exciting is that HCAR2 is not traditionally viewed as a DAMP receptor. It is best known as the receptor for niacin and β-hydroxybutyrate, thereby mediating anti-inflammatory effects in macrophages and microglia through the inhibition of NF-κB and cytokine production. The activation of HCAR2 has been shown to protect against atherosclerosis, colitis, and neurodegeneration in animal models.8 These properties raise the possibility that HCAR2 may help to mitigate heme-induced inflammation and organ injury, not only in SCD but also in intracerebral hemorrhage and other hemolytic disorders.
That said, important questions remain. Whether HCAR2 is similarly upregulated in human tissues during hemolytic crises remains an open question. It is also not yet clear how heme and known HCAR2 ligands differ in their signaling outcomes. Given that HCAR2 agonists, such as niacin, are already clinically approved, this work raises the possibility of repurposing these agents to mitigate inflammation in hemolytic disorders. However, previous clinical trials of niacin in individuals with SCD have produced no improvements in endothelial function.9
Nonetheless, the identification of HCAR2 as a heme receptor redefines the landscape of heme sensing and inflammation. By linking a well-known anti-inflammatory GPCR to a classical DAMP, Grunenwald et al uncovered a new layer of immune regulation and offered a fresh perspective on how the body maintains balance during hemolytic stress.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
