DAMPening inflammation by modulating TLR signalling

Abstract

Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.

Figure 1

Endogenous TLR activators. TLRs are activated by damage-associated molecular patterns (DAMPs) including intracellular molecules released in the extracellular milieu by activated or necrotic cells and extracellular matrix molecules either upregulated upon injury or degraded following tissue damage. Known endogenous TLR activators are listed based on their biochemical nature.

Figure 2

Endogenous ligand recognition by TLRs. The co-receptor(s) and accessory molecule(s) required by DAMPs for recognition by TLR(s) and subsequent cellular activation are shown. (a) TLRs localised on the plasma membrane; (b) TLRs resident in intracellular compartments. (*)HMGB1 may require MD-2 and CD14 for TLR4 activation (see [96]).

Figure 3

DAMPs and human disease. High levels of many DAMPs are associated with a wide variety of inflammatory and autoimmune diseases as well as with atherosclerosis and cancer.

Figure 4

The “damage chain reaction.” Harmful stimuli, including pathogens, injury, heat, autoantigens, tumor, and necrotic cells, cause tissue damage. Endogenous danger signals are generated and induce a pro-inflammatory cascade by activating TLRs. In turn, pro-inflammatory mediators are upregulated and trigger further tissue damage leading to increasing DAMPs levels. Thus a vicious cycle is sustained and may result in chronic inflammation and autoimmunity.