The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

Abstract

Silicosis remains one of the most severe pulmonary fibrotic diseases worldwide, caused by chronic exposure to silica dust. In this review, we have proposed that programmed cell death (PCD), including autophagy, apoptosis, and pyroptosis, is closely associated with silicosis progression. Furthermore, some autophagy, apoptosis, or pyroptosis-related signaling pathways or regulatory proteins have also been summarized to contribute greatly to the formation and development of silicosis. In addition, silicosis pathogenesis depends on the crosstalk among these three ways of PCD to a certain extent. In summary, more profound research on these mechanisms and effects may be expected to become promising targets for intervention or therapeutic methods of silicosis in the future.

Keywords: apoptosis; autophagy; programmed cell death; pyroptosis; silicosis.

Figure 1

Related molecular mechanisms and effects during the process of silica-induced autophagy. Silica invasion led to the accumulation of autophagosomes and the disruption of lysosomes, thereby breaking the function of autophagic degradation through the PI3K/Akt/mTOR signaling pathway. Under silica circumstances, ZC3H4 and MCPIP1 both activated autophagy activity. Concretely, ZC3H4 was enhanced not only by the up-regulation of circZC3H4, but also by the transcription of ZC3H4 mRNA via phosphorylation of Elk-1. Furthermore, the interaction of Gas6 and its receptor, Mer, boosted autophagy activity. In addition, Fe atoms were found to be accumulated on the surface of silica, which further magnified the pathological damage of the autophagic process. LPS, nicotine, and habitual smoking all led to the blockade of autophagic degradation. Specifically, TLR4/Myd88 or TLR4/TICAM signaling pathways might be involved in the autophagy induced by silica together with LPS. Particularly, natural products like tre and kea had a protective function in the degradation process of autophagic substrates. When silica invaded, dioscin removed redundant damaged mitochondria through AM mitophagy, and ATL-III protected AM autophagic degradation via an mTOR-dependent signaling pathway.

Figure 2

A complex regulatory network of initiation of silica-induced apoptosis or pyroptosis. Normally, when silica invades the alveoli, mtROS is produced and augments the formation of the cas-9-Apaf-1 complex. Furthermore, cas-3 is activated to crack PARP, leading to cell apoptosis finally. In such a mitochondrial-dependent apoptotic pathway, the increased ratio of Bax/Bcl-2 aggravates the cas-3 activation. Moreover, the Fas/FasL signaling pathway, induced by upstream factor Annexin A5, also mediates silica-induced apoptosis. p53 induces apoptosis, not via the inhibition of uPA and induction of PAI-1, but via p53 trans-activation. Another member of the p53 family, PPP1R13B, promotes over-activation of ER stress via the PERK/eIF2α/CHOP signaling pathway, further initiating silica-induced apoptosis. Similarly, it also can be activated by ER stress-related protein cas-12. Silica-induced apoptosis is still induced by the IL-1β-iNOS-NO cascade reaction. Notably, TNF-α activation aggravates cell apoptosis. However, TNF-α also stimulates the NF-κB signaling pathway to alleviate cell apoptosis against silica invasion. The bidirectional role of TNF-α deserves further discussion. It is worth noting that NAC and DHA have potential anti-apoptotic effects activated by silica. In addition to apoptosis, silica can stimulate the interaction of NALP3 and ASC, and subsequent NALP3-ASC complex activates cas-1. The cas-1 activation leads to the transformation from pro-IL-1β to IL-1β, further executing cell pyroptosis. BMSCs might mitigate cell pyroptosis via inhibition of NALP3.

Figure 3

The current molecular mechanism of crosstalk among autophagy, apoptosis, and pyroptosis under silica circumstances. Two important members of the Bcl-2 apoptotic protein family, Bcl-2 and BBC3, activate autophagy via reducing the Bcl-2–BECN1 complex in silica-induced pulmonary fibrosis. Autophagy activity is also stimulated by silica-induced ER stress. Lysosomal disruption, a critical characteristic of silica-induced autophagy, could foster the formation of the NALP3–ASC complex. It further activates cas-1, boosting the transformation from pro-IL-1β to IL-1β and executing pyroptosis. Notably, the relationship between autophagy and NALP3 or the mechanism of cas-3-mediated pyroptosis deserves more exploration.