Research Highlights

Tissue injury: CD24 and Siglec-10 DAMPen inflammation

When microbes invade a host, Toll-like receptors and other innate immune signaling molecules recognize certain pathogen-associated molecular patterns (PAMPs) unique to viruses or bacteria, including single-stranded RNA and lipopolysaccharide. This interaction triggers inflammation and the release of cytokines that help fight the infection. When cells are damaged by non-infectious causes, nuclear and cytosolic proteins can act as danger-associated molecular patterns (DAMPs) that also activate inflammatory responses through Toll-like receptor signaling. Now, in Science, Chen et al. uncover a unique signaling pathway that can distinguish DAMPs from PAMPs. Here, sialoglycoprotein CD24 recognizes DAMPs and signals through Siglec-10/G to downregulate inflammation.

To detect the cellular factors that respond to tissue damage, wild-type and CD24-deficient mice were given a non-lethal dose of acetaminophen. Wild-type mice tolerated the drug, but mice lacking CD24 experienced an increased cytokine release and a higher mortality rate, suggesting that this sialoglycoprotein protects against acetaminophen-induced liver damage. In searching for CD24 ligands, the authors pinpointed HMGB1, a nuclear protein and well-known DAMP. To test the role of HMGB1 in acetaminophen-induced liver damage, wild-type and CD24-deficient mice were treated with antibodies directed against HMGB1. Anti-HMGB1 treatment protected mice lacking CD24 from acetaminophen-induced injury and decreased mortality.

Because CD24 was able to protect against liver damage by reducing the immune response to HMGB1, the authors looked toward the Siglec family of glycan-binding proteins to identify a signaling mechanism. Siglecs, a family of membrane-bound sialic-acid-binding immunoglobulin-like lectins, typically contain at least one intracellular immune receptor tyrosine-based inhibitor motifs and are known in many cases to regulate the immune system negatively. This study revealed that Siglec-10 not only specifically binds CD24, but also recognizes HGMB1 in a CD24-dependent manner. Like CD24-deficient mice, mice lacking Siglec-G (the murine equivalent of Siglec-10) were highly susceptible to liver damage after acetaminophen treatment, and were rescued by treatment with antibodies against HMGB1. In contrast, the presence or absence of CD24 and Siglec-10/G did not affect mortality rates or cytokine responses to PAMPs.

This is the first study to identify a signaling mechanism that discriminates between infectious and non-infectious injury signals. Given that DAMP signals like HMGB1 have been implicated in a variety of diseases, including liver toxicity, exploitation of the CD24–Siglec-10 pathway could reveal novel therapeutic targets.

Author: Heather Buschman