Interplay between Gut Microbiota and NLRP3 Inflammasome in Intracerebral Hemorrhage

Abstract

The pathophysiological process of intracerebral hemorrhage (ICH) is very complex, involving various mechanisms such as apoptosis, oxidative stress and inflammation. As one of the key factors, the inflammatory response is responsible for the pathological process of acute brain injury and is associated with the prognosis of patients. Abnormal or dysregulated inflammatory responses after ICH can aggravate cell damage in the injured brain tissue. The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex distributed in the cytosol, which can be triggered by multiple signals. The NLRP3 inflammasome is activated after ICH, thus promoting neuroinflammation and aggravating brain edema. In addition, there is evidence that the gut microbiota is crucial in the activation of the NLRP3 inflammasome. The gut microbiota plays a key role in a variety of CNS disorders. Changes in the diversity and species of the gut microbiota affect neuroinflammation through the activation of the NLRP3 inflammasome and the release of inflammatory cytokines. In turn, the gut microbiota composition can be influenced by the activation of the NLRP3 inflammasome. Thereby, the regulation of the microbe-gut-brain axis via the NLRP3 inflammasome may serve as a novel idea for protecting against secondary brain injury (SBI) in ICH patients. Here, we review the recent evidence on the functions of the NLRP3 inflammasome and the gut microbiota in ICH, as well as their interactions, during the pathological process of ICH.

Keywords: NLRP3 inflammasome; gut microbiota; intracerebral hemorrhage; secondary brain injury.

Figure 1

The recognition of DAMPs and PAMPs induces a change in the NLRP3 protein structure and the exposure of its PYD domain to bind to the PYD of ASC, thus forming a PYD–PYD interaction. Then, ASC recruits the cysteine protease pro-caspase-1 to assemble the inflammasome complex via interacting with CARD. Pro-caspase-1 is activated by self-cleavage to form active caspase-1. Activated caspase-1 dissociates GSDMD and releases its N-terminal domain, which interacts with the cell membrane to produce pores and induce “pyroptosis”. In addition, caspase-1 can also induce the transformation of IL-1β and IL-18 precursors into mature IL-1β and IL-18 to induce inflammatory responses.

Figure 2

Neuroinflammation plays an important role in the process of SBI after ICH. ICH triggers NLRP3 inflammasome activation. The activation of the NF-κB signaling pathway promotes NLRP3 inflammasome activation and further promotes the release of IL-1β and IL-18 through caspase-1. The release of IL-1β and IL-18 further aggravates the neuroinflammatory response of ICH. The gut microbiota is important in the activation of the NLRP3 inflammasome. After ICH, the release of DAMPs and cytokines as well as the activation of the vagus nerve induce gut dysmotility, gut dysbiosis and increased gut permeability. Gut microbiota dysbiosis will lead to changes in microbial metabolites, especially a reduction in SCFAs. SCFAs act as energy substances and can suppress the NLRP3 inflammasome and repair the dysfunction of the intestinal barrier. ICH triggers NLRP3 inflammasome activation, changing the gut microbiota diversity and its metabolites. In turn, changes in the gut microbiota can influence neuroinflammation by activating the gut NLRP3 inflammasome and releasing inflammatory cytokines.