Microbiota, Immune Subversion, and Chronic Inflammation

Abstract

Several host-adapted pathogens and commensals have evolved mechanisms to evade the host innate immune system inducing a state of low-grade inflammation. Epidemiological studies have also documented the association of a subset of these microorganisms with chronic inflammatory disorders. In this review, we summarize recent studies demonstrating the role of the microbiota in chronic inflammatory diseases and discuss how specific microorganisms subvert or inhibit protective signaling normally induced by toll-like receptors (TLRs). We highlight our work on the oral pathogen Porphyromonas gingivalis and discuss the role of microbial modulation of lipid A structures in evasion of TLR4 signaling and resulting systemic immunopathology associated with atherosclerosis. P. gingivalis intrinsically expresses underacylated lipid A moieties and can modify the phosphorylation of lipid A, leading to altered TLR4 signaling. Using P. gingivalis mutant strains expressing distinct lipid A moieties, we demonstrated that expression of antagonist lipid A was associated with P. gingivalis-mediated systemic inflammation and immunopathology, whereas strains expressing agonist lipid A exhibited modest systemic inflammation. Likewise, mice deficient in TLR4 were more susceptible to vascular inflammation after oral infection with P. gingivalis wild-type strain compared to mice possessing functional TLR4. Collectively, our studies support a role for P. gingivalis-mediated dysregulation of innate and adaptive responses resulting in immunopathology and systemic inflammation. We propose that anti-TLR4 interventions must be designed with caution, given the balance between the protective and destructive roles of TLR signaling in response to microbiota and associated immunopathologies.

Keywords: atherosclerosis; immune dysregulation; immune subversion; inflammation; innate immunity; microbiota; toll-like receptors.

Figure 1

The role of toll-like receptor (TLR) signaling in chronic inflammation. (A) During a normal inflammatory response, activation of TLR signaling results in an increase in proinflammatory mediators and antimicrobial peptides, activation of the inflammasome, and clearance of the pathogen (97, 103, 104). Eradication of the stimulus results in resolution of inflammation (–102). Some bacteria inhibit one or more of these responses, preventing the resolution of inflammation. (B) Porphyromonas gingivalis activation of TLR2 results in decreased production of proinflammatory cytokines such as IL-12 and IFN-γ, impairing bacterial clearance (109). P. gingivalis expressing a TLR4 antagonist lipid A moiety produces low levels of IL-1β and prevents activation of the non-canonical inflammasome, which also impairs bacterial clearance (108). In contrast, P. gingivalis expressing a TLR4 agonist lipid A moiety produces high levels of IL-1β and activates the inflammasome (108).