A calculated response: control of inflammation by the innate immune system

Abstract

Inflammation is a rapid yet coordinated response that can lead to the destruction of microbes and host tissue. Triggers capable of inducing an inflammatory response include tissue damage and infection by pathogenic and nonpathogenic microbes. Each of these triggers represents a qualitatively distinct stress to the host immune system, yet our understanding of whether they are interpreted as such remains poor. Accumulating evidence suggests that recognition of these distinct stimuli converges on many of the same receptors of the innate immune system. Here I provide an overview of these innate receptors and suggest that the innate immune system can interpret the context of an inflammatory trigger and direct inflammation accordingly.

Figure 1. Pattern recognition by the innate immune system.

A schematic representation of the PRR families within the innate immune system. TLRs are transmembrane receptors, whereas Nods, Naips, Nalps, as well as the nucleic acid sensors RIG-I, MDA-5, and DAI-1 are all present in the cytosol. Most of these PRR families activate common transcription factors and induce the expression of proinflammatory genes. Members of the Nalp and Naip families control activation of the inflammasome, a multiprotein complex responsible for the processing and secretion of IL-1. Whether other PRR families can directly induce inflammasome activation remains controversial. Refer to the text for a discussion of the ligands recognized by each PRR family.

Figure 2. Cross-talk between TLR and NLR pathways.

The TLR and NLR families sense microbial ligands in different compartments within the cell. NLRs are activated by the presence of cytosolic microbes or the action of microbial virulence mechanisms. These signals feed back on the TLR transcriptional response by activating IL-1R, which activates many of the same signaling pathways as TLRs.

Figure 3. A simple model for specific gene induction in response to different inflammatory triggers.

(i) The known triggers leading to inflammation converge on similar innate receptor pathways. Whether these triggers can be distinguished by the innate immune system and lead to qualitatively distinct responses (as shown here, with blue indicating activation of genes encoding proteins that mediate repair; red indicating activation of genes encoding proteins that mediate antimicrobial inflammation, adaptive immunity, and repair; and green indicating activation of genes encoding proteins that mediate antimicrobial inflammation, increased host cell death, adaptive immunity, and repair) is an important unanswered question. (ii) Differential gene induction may lead to escalating responses and additional genes. Left: In this scenario it is possible that the genes induced by tissue damage (blue) and microbial infection (red) are subsets of the full response induced by pathogenic microbes (green). Right: Alternatively, tissue repair (blue) might induce a qualitatively distinct response to microbial infection (red) and pathogenic microbes (green), skewed toward repair. See text for discussion.