Macrophage Autophagy and Silicosis: Current Perspective and Latest Insights

Abstract

Silicosis is an urgent public health problem in many countries. Alveolar macrophage (AM) plays an important role in silicosis progression. Autophagy is a balanced mechanism for regulating the cycle of synthesis and degradation of cellular components. Our previous study has shown that silica engulfment results in lysosomal rupture, which may lead to the accumulation of autophagosomes in AMs of human silicosis. The excessive accumulation of autophagosomes may lead to apoptosis in AMs. Herein, we addressed some assumptions concerning the complex function of autophagy-related proteins on the silicosis pathogenesis. We also recapped the molecular mechanism of several critical proteins targeting macrophage autophagy in the process of silicosis fibrosis. Furthermore, we summarized several exogenous chemicals that may cause an aggravation or alleviation for silica-induced pulmonary fibrosis by regulating AM autophagy. For example, lipopolysaccharides or nicotine may have a detrimental effect combined together with silica dust via exacerbating the blockade of AM autophagic degradation. Simultaneously, some natural product ingredients such as atractylenolide III, dioscin, or trehalose may be the potential AM autophagy regulators, protecting against silicosis fibrosis. In conclusion, the deeper molecular mechanism of these autophagy targets should be explored in order to provide feasible clues for silicosis therapy in the clinical setting.

Keywords: alveolar macrophage; autophagy; silicosis.

Figure 1

The general silicosis pathological mechanism. The attack of silica dust triggers the phagocytosis of alveolar macrophages (AMs). However, the lysosomal membrane of AM will be disrupted by the H-bonding reaction, causing AM apoptosis. Notably, AM apoptosis may be regulated by the mitochondria apoptotic pathway, Fas apoptotic pathway, nuclear factor kappa-B (NF-κB) apoptotic pathway, and p53 apoptotic pathway. Apoptotic AM secrets a series of inflammatory factors. Eventually, the proliferation, activation, and migration of fibroblasts synthesize and release collagen, resulting in silicosis fibrosis.

Figure 2

Determined mechanism of silicosis pathogenesis mediated by macrophage autophagy. (a) Normally, the pre-autophagosomal structure (PAS) begins to engulf cytosolic components, following which the signal of autophagy is activated. Subsequently, the autophagosomal membrane expands, matures, and closes gradually. Once closed, the autophagosome will fuse with the lysosome to form the autophagolysosome, degrading its wrapped contents. Several autophagy-related proteins act critically, indicating effect during the process of autophagy. Sequestosome 1 (p62/SQSTM1) interacts with ubiquitinated substrates, participating in the subsequent process of autophagic degradation. Microtubule-associated protein 1A/1B-light chain 3-I (LC3-I) conjugates with phosphatidylethanolamine to form LC3-II, involved in the expansion, maturation, and closure of autophagosome. Additionally, lysosome-associated membrane protein (LAMP) is attached to the surface of the lysosome. (b) When invading macrophages (especially alveolar macrophages) excessively, silica dust will cause autophagosomes to accumulate and lysosomes to disrupt (i.e., the dysfunction of the autophagy-lysosomal system). (c) Silica dust invades macrophages (especially alveolar macrophages) via a class A scavenger receptor (SR-A) and causes the blockade of autophagic degradation. The impairment of autophagy function caused by silica further leads to excessive macrophage apoptosis by decreasing the level of BCL2 and increasing the level of BCL2-Associated X (Bax). The inflammation and subsequent silicosis fibrosis occur eventually. Notably, nuclear transfer of nuclear factor kappa-B (NF-κB) may be an important link between autophagy and apoptosis in silicosis. In this pathological progression, disruption of the autophagy-lysosomal system induces macrophage apoptosis through the activation of NACHT-, LRR-, and PYD domain-containing protein 3 (NALP3). NALP3 also increases macrophage apoptosis via the nuclear transfer of NF-κB. Meanwhile, activation of BCL2-binding component 3 (BBC3) or Monocyte chemoattractant protein-1-induced protein 1 (MCPIP1) promotes macrophage apoptosis through exacerbating the autophagic degradation. However, the functional role of Toll-like receptor 4 (TLR4) is still controversial.