Silent Killer: how the innate immune receptor Clec12a defends against potentially harmful microbes without excessive inflammation 3381

Description We are constantly exposed to a vast range of microbes starting at birth, some beneficial, others benign, and still others pathogenic. Our immune system must not only maintain tolerance to this complex community of microorganisms that becomes our microbiota but also defend against any pathogens. How our immune system does this without excess inflammation remains vastly unknown. We have determined that the innate immune receptor Clec12a, functions at the cusp of these two functions within the intestine. This pattern recognition receptor (PRR) is unique in that unlike other PRRs that mount pro-inflammatory responses, Clec12a does the opposite. It inhibits pro-inflammatory signaling downstream of other PRRs. Mice lacking Clec12a get worsened colitis, and upon analysis of the Clec12a-/- intestinal microbiota composition, we see an outgrowth of the bacteria Faecalibaculum rodentium, which, if administered to WT mice, can drive worsened colitis, suggesting that it has pathogenic qualities. We find that Clec12a can bind specific intestinal bacteria and that, upon binding is involved in phagocytosis, resulting in microbiota compositional changes. Further, when Clec12a-/- macrophages are stimulated with F. rodentium, these macrophages exhibit significantly more pro-inflammatory cytokine production. Together, these data suggest that Clec12a acts as a silent killer within the intestine, binding potentially harmful microbes and removing them without eliciting excessive inflammation.