Inhibitory Effects of the Lactobacillus rhamnosus GG Effector Protein HM0539 on Inflammatory Response Through the TLR4/MyD88/NF-кB Axis

Abstract

Inflammatory bowel disease (IBD) is a chronic and relapsing intestinal inflammatory condition with no effective treatment. Probiotics have gained wide attention because of their outstanding advantages in intestinal health issues. In previous studies, a novel soluble protein, HM0539, which is derived from Lactobacillus rhamnosus GG (LGG), showed significant protective effects against murine colitis, but no clear precise mechanism for this effect was provided. In this study, we hypothesized that the protective function of HM0539 might be derived from its modulation of the TLR4/Myd88/NF-κB axis signaling pathway, which is a critical pathway widely involved in the modulation of inflammatory responses. To test this hypothesis, the underlying anti-inflammatory effects and associated mechanisms of HM0539 were determined both in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and in dextran sulfate sodium (DSS)-induced murine colitis. Our results showed that HM0539 inhibited the expression of cyclooxygenase-2 (COX-2) and the expression inducible nitric oxide synthase (iNOS) by down-regulating the activation of their respective promoter, and as a result this inhibited the production of prostaglandin E2 (PGE2) and nitric oxide (NO). Meanwhile, we demonstrated that HM0539 could ultimately modulate the activation of distal NF-κB by reducing the activation of TLR4 and suppressing the transduction of MyD88. However, even though the overexpression of TLR4 or MyD88 obviously reversed the effect of HM0539 on LPS-induced inflammation, HM0539 still retained some anti-inflammatory activity. Consistent with the in vitro findings, we found that HM0539 inhibited to a great extent the production of inflammatory mediators associated with the suppression of the TLR4/Myd88/NF-κB axis activation in colon tissue. In conclusion, HM0539 was shown to be a promising anti-inflammatory agent, at least in part through its down-regulation of the TLR4-MyD88 axis as well as of the downstream MyD88-dependent activated NF-κB signaling, and hence might be considered as a potential therapeutic option for IBD.

Kaempferol Alleviates Murine Experimental Colitis by Restoring Gut Microbiota and Inhibiting the LPS-TLR4-NF-κB Axis

“…Upon ligand binding, MyD88-dependent signaling can result in the phosphorylation of NF-kB, a transcription factor that regulates the levels of IL-1b, IL-6, TNF-a, and several other inflammatory factors, in response to NLRP3 (53,54). Consistent with previous investigations (55,56), our study showed that Kae could inhibit the expression of inflammatory-associated mediators by dampening the activation of the LPS-TLR4-NF-kB signaling in mice with DSStriggered colitis.…”

Lactobacillus rhamnosus GG Derived Extracellular Vesicles Modulate Gut Microbiota and Attenuate Inflammatory in DSS-Induced Colitis Mice

“…Therefore, inhibiting TLR4 signaling can effectively regulate the expression levels of inflammatory cytokines induced by DSS. It had been reported that L. rhamnosus GG or L. rhamnosus GG-derived factors could attenuate the inflammatory response induced by activation of TLR4/NF-κB in the colitis [34,35]. In our current research, we found LGG-EVs had the same anti-inflammatory effect, which was accomplished by downregulating the expression of myd88, p65, and p-p65 via inhibiting TLR4 signaling.…”

Lactiplantibacillus plantarum HG20 attenuates II type collagen-induced rheumatoid arthritis in rats via anti-inflammatory and inhibition of apoptosis

“…TLR4/MYD88/NF-κB signalling pathway plays an important role in the development of RA through the secretion of pro-inflammatory cytokines and matrix metallopeptidase (Kim et al, 2018). The key signalling pathway of TLR4 mediated inflammatory response has been confirmed in the studies of probiotics to improve the inflammation of various diseases (Li et al, 2020;Yu et al, 2020). This study showed that compared with the model group, HG20 could significantly decrease the expression levels of TLR4, MyD88 and NF-κB and IκB-α proteins.…”