Caspase-1-mediated extracellular vesicles derived from pyroptotic alveolar macrophages promote inflammation in acute lung injury

Abstract

The occurrence and development of acute lung injury (ALI) involve a variety of pathological factors and complex mechanisms. How pulmonary cells communicate with each other and subsequently trigger an inflammatory cascade remains elusive. Extracellular vesicles (EVs) are a critical class of membrane-bound structures that have been widely investigated for their roles in pathophysiological processes, especially in immune responses and tumor progression. Most of the current knowledge of the functions of EVs is related to functions derived from viable cells (e.g., microvesicles and exosomes) or apoptotic cells (e.g., apoptotic bodies); however, there is limited understanding of the rapidly progressing inflammatory response in ALI. Herein, a comprehensive analysis of micron-sized EVs revealed a mass production of 1-5 μm pyroptotic bodies (PyrBDs) release in the early phase of ALI induced by lipopolysaccharide (LPS). Alveolar macrophages were the main source of PyrBDs in the early phase of ALI, and the formation and release of PyrBDs were dependent on caspase-1. Furthermore, PyrBDs promoted the activation of epithelial cells, induced vascular leakage and recruited neutrophils through delivery of damage-associated molecular patterns (DAMPs). Collectively, these findings suggest that PyrBDs are mainly released by macrophages in a caspase-1-dependent manner and serve as mediators of LPS-induced ALI.

Pyroptosis in inflammation-related respiratory disease

“…Additionally, pyroptosis mediated by anthrax lethal toxin-activated NLRP1 inflammasome in AMs promotes lung inflammation and results in the exacerbation of ALI [ 32 ]. Furthermore, growing evidence suggests that pyroptosis may also trigger the enhanced inflammatory response in ALI by generating pyroptotic bodies (PyrBDs), which are mainly derived from pyroptotic AMs [ 52 ]. PyrBDs, which contain substantial DAMPs, trigger vascular interstitial edema and neutrophil recruitment [ 52 ].…”

Extracellular vesicles in the pathogenesis and treatment of acute lung injury

“…Conversely, M2 macrophages secrete anti-inflammatory and pro-angiogenic factors and phagocytose apoptotic cells to promote tissue remodeling [ 53 , 55 ]. Further, in an LPS-induced mouse ALI model, alveolar macrophages were reported to release pyroptotic bodies containing damage-associated molecular patterns that could mediate pulmonary inflammation by promoting epithelial cell activation, inducing vascular leakage, and recruiting neutrophils [ 56 ]. Therefore, inhibiting this pro-inflammatory macrophages response by promoting macrophage M1 to M2 polarization [ 57 ], inhibiting NLRP3 inflammasome activation and macrophage apoptosis [ 58 ], and inducing macrophage mitophagy to prevent pyroptosis [ 59 ] may be effective strategies to reduce lung inflammation.…”

Pyroptosis and respiratory diseases: A review of current knowledge

“…Furthermore, growing evidence suggests that pyroptosis may also enhance the inflammatory response in ALI by generating pyroptotic bodies (PyrBDs) which are released by macrophages in a Caspase-1dependent manner. PyrBDs serve as mediators of LPS-induced ALI by triggering vascular interstitial edema and recruiting neutrophils (152). In addition to bacteria, viruses can also induce ALI, and some severe cases have serious complications, such as systemic inflammatory response characterized by the release of inflammatory cytokines, ARDS, respiratory failure, and so on (153).…”