SIGNR 3‐dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis

Abstract

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 À/À 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.

Commensal Propionibacterium strain UF1 mitigates intestinal inflammation via Th17 cell regulation

“…Bacterial dihydrolipoamide acetyltransferase drives Th17 cells. Sensing receptor interactions with the bacterial surface layer (S-layer) stimulate intestinal DCs, leading to T cell activation (31)(32)(33)(34). Activated T cells, in general, and antigen-specific Th17 cells, in particular, are tightly controlled by gut commensals, including segmented filamentous bacteria (SFB) (35,36) along with regulated cytokines (e.g., IL-6, TGF-β, IL-1β) (37).…”

Advancing the use ofLactobacillus acidophilussurface layer protein A for the treatment of intestinal disorders in humans

“…L. acidophilus-SlpA isolation by NaCl. L. acidophilus-SlpA was isolated and purified, as described previously, 23 with substitution of LiCl with NaCl. (A) SDS-PAGE containing 2.5 mg of LiCl¡ and NaCl¡isolated SlpA stained with Coomassie blue to visualize the purified protein.…”

“…20,21,22 To specifically determine the effects of SlpA and its binding to SIGNR3 on intestinal cells, and the consequences thereafter, the upp counter-selective knockout strategy 10 was used to generate a new strain of L. acidophilus, called NCK2187, which expresses only SlpA on its surface. 23 This new bacterial strain was critical to definitively elucidate the role of SlpA in controlling pathogenic inflammation, as oral treatment with purified SlpA or the bacteria expressing only SlpA on their surfaces resulted in significant clinical improvement of murine colitis. Furthermore, our data showed that SlpA plays a critical role in controlling immune responses upon its interaction with SIGNR3, resulting in the amelioration of induced colitis, protection of intestinal barrier integrity, and maintenance of the gut bacterial composition.…”

“…Furthermore, our data showed that SlpA plays a critical role in controlling immune responses upon its interaction with SIGNR3, resulting in the amelioration of induced colitis, protection of intestinal barrier integrity, and maintenance of the gut bacterial composition. 23 To build upon these observations, we have optimized the purification of SlpA to investigate its physiological effects when orally administrated to mice, and have evaluated whether this protein is able to resist the harsh conditions of the GI microenvironment, both important factors that may affect the feasibility of its use in potential clinical trials.…”

Lactobacillus acidophilus, un futur outil thérapeutique dans le traitement des maladies inflammatoires chroniques de l’intestin ?

“…Les chercheurs avaient ainsi postulé que cette protéine glycosylée pourrait être reconnue par la lectine de type C DC-SIGN, exprimée par les cellules dendritiques, dont on sait qu'elle contrôle la régulation des réponses immunitaires [12]. Dans une étude plus récente, Lightfoot et al ont maintenant démontré que ceci est le cas [13]. Ils ont utilisé une souche de L. acidophilus (appelée NCK2187) exprimant SlpA mais pas d'autres composants de surface tels que LspB, LspX et LTA, et des souris dont le gène SignR3, qui code pour un homologue murin de DC-SIGN, a été inactivé.…”