Tlr9, or Toll-like receptor 9, is an intracellular pattern recognition receptor integral to the innate immune system. It recognizes unmethylated CpG DNA motifs, initiating signaling pathways that regulate production of proinflammatory cytokines, type I interferons, and other molecules crucial for the immune response. TLR9-mediated signaling not only activates innate immune cells but also mounts acquired responses, and is involved in maintaining physiological homeostasis [1,2,3].

In mouse models, genetic dissection of Tlr9 in lupus-prone MRL/lpr mice generated two point mutants (Tlr9K51E lacking ligand binding and Tlr9P915H lacking MyD88 binding). The Tlr9K51E mice showed ameliorated disease compared to Tlr9-/-controls, revealing a ligand-and MyD88-independent “scaffold” protective function of TLR9. Unexpectedly, Tlr9P915H mice were more protected, suggesting TLR9 has ligand-dependent but MyD88-independent regulatory signaling and MyD88-mediated proinflammatory signaling. Triple-mixed bone marrow chimeras showed TLR9-MyD88-independent regulatory roles were B cell intrinsic, restraining differentiation into pathogenic age-associated B cells and plasmablasts [4].

In conclusion, Tlr9 is a key receptor in the immune response, playing important roles in inflammation, immunity, and homeostasis. The genetic models in mouse lupus have revealed complex regulatory and proinflammatory roles of Tlr9, contributing to our understanding of the biology of endosomal TLRs and the pathogenesis of autoimmune diseases like lupus.