SIGNR3-dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis

Intestinal immune regulatory signals govern gut homeostasis. Breakdown of such regulatory mechanisms may result in inflammatory bowel disease (IBD). Lactobacillus acidophilus contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA), which interact with pattern recognition receptors to mobilize immune responses. Here, to elucidate the role of SlpA in protective immune regulation, the NCK2187 strain, which solely expresses SlpA, was generated. NCK2187 and its purified SlpA bind to the C-type lectin SIGNR3 to exert regulatory signals that result in mitigation of colitis, maintenance of healthy gastrointestinal microbiota, and protected gut mucosal barrier function. However, such protection was not observed in Signr3^-/- mice, suggesting that the SlpA/SIGNR3 interaction plays a key regulatory role in colitis. Our work presents critical insights into SlpA/SIGNR3-induced responses that are integral to the potential development of novel biological therapies for autoinflammatory diseases, including IBD. Synopsis Functional intestinal homeostasis is tightly controlled by the interaction of gut microbial gene products with pattern recognition receptors, including C-type lectins. Bacterial SlpA via interaction with SIGNR3, the human DC-SIGN ortholog, controls proinflammation by reducing critical proinflammatory signals, thereby allowing the differentiation of extrathymic regulatory T cells (Tregs) and the mitigation of colitis. Interruption of SlpA:SIGNR3 interaction leads to the dysfunction of intestinal homeostasis and the formation of proinflammatory innate cells and Tregs. The Lactobacillus acidophilus surface layer protein SlpA protects mice against T-cell-, DSS-, and infection-induced colitis. SlpA enhances the intestinal barrier and the gut microbiota, and regulates immune responses in steady state and in disease. SlpA binds to murine C-type lectins, SIGNR3, and its human ortholog DC-SIGN. Protection by SlpA is highly controlled by SIGNR3 signaling. C-lectin binding of the L. acidophilus surface layer glycoprotein SlpA protects against experimental colitis in mice by preventing mucosal inflammation, microbial dysbiosis, and barrier dysfunction.