Patients with SCD have high levels of proinflammatory cytokines, which can potentiate SCD sequalae. The work by Allali et al demonstrates that cell-free HbS induces high levels of proinflammatory cytokine production by monocytes. The authors further elucidate the pathway by showing that HbS, although differing by only one amino acid from HbA, has high affinity for the TLR4/MD-2 complex. On ligation of HbS to the TLR4/MD-2 complex, downstream signaling induces NF-κB activation and subsequent proinflammatory cytokine production.