The sterile inflammatory response

Abstract

The acute inflammatory response is a double-edged sword. On the one hand, it plays a key role in initial host defense, particularly against many infections. On the other hand, its aim is imprecise, and as a consequence, when it is drawn into battle, it can cause collateral damage in tissues. In situations where the inciting stimulus is sterile, the cost-benefit ratio may be high; because of this, sterile inflammation underlies the pathogenesis of a number of diseases. Although there have been major advances in our understanding of how microbes trigger inflammation, much less has been learned about this process in sterile situations. This review focuses on a subset of the many sterile stimuli that can induce inflammation-specifically dead cells and a variety of irritant particles, including crystals, minerals, and protein aggregates. Although this subset of stimuli is structurally very diverse and might appear to be unrelated, there is accumulating evidence that the innate immune system may recognize them in similar ways and stimulate the sterile inflammatory response via common pathways. Here we review established and emerging data about these responses.

Figure 1

Source and role of IL-1 in recruiting neutrophils to sterile cell death. IL-1α in necrotic cells can be released and directly activate parenchmal (radioresistant) cells. In addition, necrotic cells release DAMPs (damage associated molecular patterns) that are recognized by macrophages, which in turn produce IL-1α and IL-1β to stimulate parenchymal cells. IL-1-stimulated parenchymal cells secrete chemokines to recruit neutrophils.

Figure 2

The NLRP3 Inflammasome. The NLRP3 inflammasome is a heterotrimeric protein complex composed of NLRP3, the apoptosis associated speck-like protein (ASC) and pro-caspase I. Its NLRP3 subunit is composed of three distinct domains. One of these is a leucine-rich repeat region (LRR) that is thought to be involved in ligand recognition. The two other domains, NACHT and Pyrin-domain (PYD), are involved in protein-protein interactions. The PYD domain of NLRP3 binds to the PYD domain in ASC. Using its CARD domain, ASC recruits pro-caspase 1. This complex assembles in the cytosol of cells. Upon activation it cleaves and releases activated caspase-1, which then cleaves pro-IL-1β into its mature and active form.

Figure 3

Phagolysosome disruption and activation of the inflammasome. Phagosomes containing sterile particles acidify, generate reactive oxygen species (ROS) and then some of these vesicles rupture. The ROS that are produced have been implicated in the activation of NLRP3 inflammasomes through an unknown mechanism, possibly involving phagosomal destabilization or direct stimulation of NLRP3. The rupture of phagosomes releases activated cathepsins that trigger the NLRP3 inflammasome, possibly by cleaving an endogenous NLRP3 ligand into an active form. Dashed lines and question marks are hypothetical steps in this pathway.