Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA

Abstract

The human gut microflora is important in regulating host inflammatory responses and in maintaining immune homeostasis. The cellular and molecular bases of these actions are unknown. Here we describe a unique anti-inflammatory mechanism, activated by nonpathogenic bacteria, that selectively antagonizes transcription factor NF-kappaB. Bacteroides thetaiotaomicron targets transcriptionally active NF-kappaB subunit RelA, enhancing its nuclear export through a mechanism independent of nuclear export receptor Crm-1. Peroxisome proliferator activated receptor-gamma (PPAR-gamma), in complex with nuclear RelA, also undergoes nucleocytoplasmic redistribution in response to B. thetaiotaomicron. A decrease in PPAR-gamma abolishes both the nuclear export of RelA and the anti-inflammatory activity of B. thetaiotaomicron. This PPAR-gamma-dependent anti-inflammatory mechanism defines new cellular targets for therapeutic drug design and interventions for the treatment of chronic inflammation.

Mechanism of pathogen‐specific TLR4 activation in the mucosa: Fimbriae, recognition receptors and adaptor protein selection

“…Two different paradigms have been proposed to explain the apparent inertia of mucosal surfaces to the [12,13]. It is unclear, however, which receptors are engaged, how TLR4 is involved, which adaptors are recruited, and how the reduction in NF-jB comes about.…”

“…In vitro studies of gut epithelial cells have suggested that commensals actively inhibit the epithelial response by disrupting NF-jB-dependent transcription mechanisms [12,13]. It is unclear, however, which receptors are engaged, how TLR4 is involved, which adaptors are recruited, and how the reduction in NF-jB comes about.…”

“…Epithelial cells must be protected from constant TLR activation by commensals and their PAMP, in order for mucosal integrity to be maintained. The epithelial cells thus lack co-receptors like CD14 [6][7][8][9][10][11], and in addition, commensals have been suggested to actively suppress epithelia responses through NF-jB [12,13]. Yet, mucosal pathogens evoke rapid TLR4-dependent responses at mucosal sites, suggesting that alternative ligands and receptors might be involved in mucosal TLR activation.…”

“…Here we show that virulence-associated adherence mechanisms offer a solution to specific pathogen recognition by mucosal TLR4. In addition, the adhesive interaction was shown to influence the adaptor protein usage and the outcome of infection.Two different paradigms have been proposed to explain the apparent inertia of mucosal surfaces to the [12,13]. It is unclear, however, which receptors are engaged, how TLR4 is involved, which adaptors are recruited, and how the reduction in NF-jB comes about.…”

Genes involved in obesity: Adipocytes, brain and microflora

“…Recently Neish et al (2000) demonstrated that avirulent Salmonella abrogates production of inflammatory cascade by inhibiting ubiquitination and degradation of IkB, thus blocking the transactivation of NFkB-mediated genes. More recently, Kelly et al (2004) identified an interesting mechanism by which commensal flora may regulate host inflammatory responses and maintain immune homeostasis, by promoting nuclear export of NFkB subunit relA, through a PPAR-γ-dependent pathway. Similarly, Rakoff-Nahoum et al (2004) demonstrated that recognition of commensal microflora by Toll-like receptors is required for intestinal homeostasis, explaining why disequilibrium in this signalling pathway can lead to the initiation of inflammatory bowel diseases.…”