Macrophage cytokine responses to commensal Gram-positive Lactobacillus salivarius strains are TLR2-independent and Myd88-dependent

Abstract

The mechanisms through which cells of the host innate immune system distinguish commensal bacteria from pathogens are currently unclear. Toll-like receptors (TLRs) are a class of pattern recognition receptors (PRRs) expressed by host cells which recognize microbe-associated molecular patterns (MAMPs) common to both commensal and pathogenic bacteria. Of the different TLRs, TLR2/6 recognize bacterial lipopeptides and trigger cytokines responses, especially to Gram-positive and Gram-negative pathogens. We report here that TLR2 is dispensable for triggering macrophage cytokine responses to different strains of the Gram-positive commensal bacterial species Lactobacillus salivarius. The L. salivarius UCC118 strain strongly upregulated expression of the PRRs, Mincle (Clec4e), TLR1 and TLR2 in macrophages while downregulating other TLR pathways. Cytokine responses triggered by L. salivarius UCC118 were predominantly TLR2-independent but MyD88-dependent. However, macrophage cytokine responses triggered by another Gram-positive commensal bacteria, Bifidobacterium breve UCC2003 were predominantly TLR2-dependent. Thus, we report a differential requirement for TLR2-dependency in triggering macrophage cytokine responses to different commensal Gram-positive bacteria. Furthermore, TNF-α responses to the TLR2 ligand FSL-1 and L. salivarius UCC118 were partially Mincle-dependent suggesting that PRR pathways such as Mincle contribute to the recognition of MAMPs on distinct Gram-positive commensal bacteria. Ultimately, integration of signals from these different PRR pathways and other MyD88-dependent pathways may determine immune responses to commensal bacteria at the host-microbe interface.

Lactobacillus salivarius UCC118™ Dampens Inflammation and Promotes Microbiota Recovery to Provide Therapeutic Benefit in a DSS-Induced Colitis Model

“…UCC118™ exposure was observed to produce an M2-type phenotype in macrophages, with upregulation of M2 differentiation markers such as Fizz1, downregulation of M1 marker Nos2 and increase in IL-10 secretion. These observations are corroborated by a recent study by Udayan et al, where UCC118™ stimulated IL-10, TNFα, IL-12 and IL-6 production by macrophages in a TLR2-independent but MyD88-dependent manner [ 22 ]. Similar observations have also been made for UCC118™ treatment in murine bone marrow-derived dendritic cells [ 23 ].…”

Growth faltering regardless of chronic diarrhea is associated with mucosal immune dysfunction and microbial dysbiosis in the gut lumen

“…In the Ileum this included a positive correlation between Lactobacillus abundance and Ileal Macrophages. Lactobacillus strains have also been shown to activate macrophages in the small intestine 67 , 68 . The increased abundance of Lactobacillus salivarius in the small and large intestine of GF-DX infants coupled with increased frequency of activated macrophages suggest an infiltration of oral microbes into the small intestine resulting in activation of the innate immune system.…”

Lactobacillus: Friend or Foe for Systemic Lupus Erythematosus?

“…Moreover, the NF-κB pp65 and TLR2-dependent signaling were also increased by treatment with the strains ( 51 ). In addition, Lactobacillus salivarius strains induced cytokine responses that are Toll-like receptor2 (TLR2) independent but myeloid differentiation primary response88 (MyD88) dependent in both human and mouse macrophages with the upregulation of Tlr1, Tlr2 and Clec4e PRR genes ( 52 ). TLR-MyD88 pathway has been proved to be involved in the pathogenesis of SLE ( 53 , 54 ).…”