Single-nucleotide polymorphisms (SNPs) in the ITGAM gene (which encodes the adhesion molecule CD11b) are associated with an increased risk of systemic lupus erythematosus (SLE). Faridi et al. show that ITGAM SNPs that reduce CD11b function correlate with elevated activity of pro-inflammatory IFN-1 in patients with SLE. Furthermore, pharmacological activation of CD11b protected lupus-prone mice from end-organ injury and reduced pro-inflammatory IFN-1 responses by suppressing Toll-like receptor signalling. The researchers suggest that CD11b could be a target for therapeutic strategies to treat SLE.