Pillon NJ, Bilan PJ, Fink LN, Klip A. Cross-talk between skeletal muscle and immune cells: muscle-derived mediators and metabolic implications.

SummaryHumans and other mammals coexist with a diverse array of microbes colonizing the intestine, termed the microflora. The relationship is symbiotic, with the microbes benefiting from a stable environment and nutrient supply, and the host gaining competitive exclusion of pathogens and continuously maintenance of the gut immune homeostasis. Here we report novel crosstalk mechanisms between the human enterocyte cell line, Caco2, and underlying human monocyte-derived DC in a transwell model where Gram-positive (G + ) commensals prevent Toll-like receptor-4 (TLR4)-dependent Escherichia coli-induced semimaturation in a TLR2-dependent fashion. These findings add to our understanding of the hypo-responsiveness of the gut epithelium towards the microflora. Gut DC posses a more tolerogenic phenotype than conventional DC. Here we show that Caco2 spent medium (SM) induces tolerogenic DC with lower expression of maturation markers, interleukin (IL)-12p70, and tumour necrosis factor-a when matured with G + and Gram-negative (G -) commensals, while IL-10 production is enhanced in DC upon encountering G + commensals and reduced upon encountering G -bacteria. The Caco2 SM-induced tolerogenic phenotype is also seen in DC priming of naive T cells with elevated levels of transforming growth factor-b (TGF-b) and markedly reduced levels of bacteria-induced interferon-c production. Caco2 cell production of IL-8, thymic stromal lymphopoietin (TSLP) and TGF-b increases upon microbial stimulation in a strain dependent manner. TSLP and TGF-b co-operate in inducing the tolerogenic DC phenotype but other mediators might be involved.

Summary The gut microbiota is vital in the maintenance of homeostasis in the gut immune system. Its diversity and composition play major roles in relation to allergies and inflammatory bowel diseases, and administration of lactic acid bacteria (LAB), such as lactobacilli and bifidobacteria, has positive effects on these pathologies. However, the mechanisms behind the beneficial effects are largely unknown. Here we reveal divergent roles played by Toll‐like receptor‐2 (TLR2) and nucleotide‐binding oligomerization domain‐2 (NOD2) in dendritic cell (DC) recognition of LAB. Murine bone‐marrow‐derived DC lacking NOD2 produce higher levels of interleukin‐10 (IL‐10) and reduced levels of IL‐12 and tumour necrosis factor‐α (TNF‐α) in response to LAB. This indicates that peptidoglycan is partly responsible for the T helper type 1 skewing effect of certain LAB. Dendritic cells that are TLR2−/− produce less IL‐12 and TNF‐α and more IL‐10 in response to some strains of lactobacilli, while they produce more IL‐12 and less IL‐10 in response to bifidobacteria. The same tendency was found in human monocyte‐derived DC. We have previously reported that the weak IL‐12‐inducing and TNF‐α‐inducing bifidobacteria inhibit the T helper type 1 skewing effect induced by strong immunostimulatory lactobacilli. Here we show that this immunoinhibitory effect of bifidobacteria is dependent on TLR2 and independent of NOD2. Moreover, independently of the cytokine pattern induced by intact LAB, cell wall fractions of all LAB, as well as synthetic lipoproteins possess immunoinhibitory capacities in both human and murine DC. These novel findings suggest that LAB act as immunoregulators through interaction of lipoprotein with TLR2 and as immunostimulators through interaction of peptidoglycan with NOD2.