Restraint of inflammatory signaling by interdependent strata of negative regulatory pathways

Abstract

Activation of Toll-like receptor (TLR) signaling and related pathways by microbial products drives inflammatory responses, host-defense pathways and adaptive immunity. The cost of excessive inflammation is cell and tissue damage, an underlying cause of many acute and chronic diseases. Coincident with activation of TLR signaling, a plethora of anti-inflammatory pathways and mechanisms begin to modulate inflammation until tissue repair is complete. Whereas most studies have focused on the signaling components immediately downstream of the TLRs, this Review summarizes the different levels of anti-inflammatory pathways that have evolved to abate TLR signaling and how they are integrated to prevent cell and tissue destruction.

Figure 1

Negative regulation of IL-1β production, signaling and bioavailability as an example of multi-tiered anti-inflammatory integration. IL-1β is inhibited by at least eight interrelated mechanisms including the initial counter-regulation of TLR signaling, sustained TTP activity via DUSP1, transcription by IL-10, mRNA processing by TTP and related mRNA binding proteins (regulated by IL-10), the type I IFN-mediated inhibition of the NLRP3 inflammasome, autophagy regulation by Atg16L1, autophagy-mediated destruction of inflammasomes and then the signaling and bioavailability of IL-1β itself. Several levels of IL-1β regulation are discussed in detail in the text.

Figure 2

Three fundamental levels for transcriptional suppression of inflammation (Stratum 5). (a) Transcription factors induced during the inflammatory response, such as ATF-3 and IκBα, modulate feedback inhibition on the inducing gene. (b) Constitutively expressed factors, like Bcl-6 and NuRD, have sentinel effects on selected genes and limitation the transcriptional response. (c) Resistance to activation is acquired by suppressing TLR signaling or through creation of a repressive chromatin structure that may involve histone deacetylation and blockade of SWI/SNF-mediated activation. Secreted factors, such as IL-10, can promote transcriptional inhibition in different time frames: induced feedback mechanism (a) or a constitutively acting mechanism that limits the potency of activation (b), i.e. in the intestines, depending on context.

Figure 3

IL-10 regulates the production of downstream factors that control multiple strata of inflammation. Shown are a subset of known factors induced by IL-10 in a STAT3-dependent way and their known or speculated effects on inflammation. IL-10, via STAT3 also induces further IL-10 production in a self-reinforcing loop. The production of IL-10 by myeloid cells has been described in detail by Saraiva and O'Garra, from which this diagram was inspired.