Macrophage pyroptosis and its crucial role in ALI/ARDS

Abstract

Acute lung injury(ALI)/acute respiratory distress syndrome(ARDS) is a severe clinical syndrome characterized by high morbidity and mortality, primarily due to lung injury. However, the pathogenesis of ALI/ARDS remains a complex issue. In recent years, the role of macrophage pyroptosis in lung injury has garnered extensive attention worldwide. This paper reviews the mechanism of macrophage pyroptosis, discusses its role in ALI/ARDS, and introduces several drugs and intervening measures that can regulate macrophage pyroptosis to influence the progression of ALI/ARDS. By doing so, we aim to enhance the understanding of the mechanism of macrophage pyroptosis in ALI/ARDS and provide novel insights for its treatment.

Keywords: ALI (acute lung injury); ARDS (acute respiratory distress syndrome); macrophage - cell; pyroptosis; treatment.

Figure 1

Pathological features of ALI/ARDS. The pathologic features of ALI/ARDS include diffuse necrosis of alveolar capillary endothelial cells and epithelial cells, increased permeability of the pulmonary capillary endothelial and alveolar epithelial barriers, accumulation of protein-rich edema fluid, extensive pulmonary hemorrhage, and thrombosis in the alveolar hyaloid membrane and capillaries.

Figure 2

Molecular mechanism of pyroptosis. In the canonical inflammasome pathway, the majority of inflammasome complex is assembled from intracellular sensor protein, adapter proteins ASC and effector protein caspase. When PAMPs or DAMPs such as toxins, bacteria, viruses and dsDNA intrude, the NLRP1 and NAIP/NLRC4 can directly convert pro-caspase-1 into active caspase-1 because both of them have the CARD to connect with pro-caspase-1, while the AIM2, NLRP3, PYRIN and NLRP6 have to bind with ASC firstly before activating the pro-caspase-1 due to the lack of CARD. Active caspase-1 cleaves the GSDMD to causing damage to cell membrane and formation of perforations meanwhile cleaves pro-IL-1β and pro-IL-18 and results in the maturation of IL-1β and IL-18 that are subsequently released from the N-GSDMD pores. In the non-canonical inflammasome pathway, LPS directly binds to pro-caspase-4/5/11, resulting in activation of caspase-4/5/11, which cleaves GSDMD to trigger pyroptosis. In the granzyme-A/B-dependent pyroptosis pathway, GzmA and GzmB from NK cells and CD8 + T cells enter cancer cells via perforin and recognise GSDMB and GSDME, respectively, to induce pyroptosis. In addition, chemotherapeutic drugs and Y. pestis trigger pyroptosis through the caspase-3/GSDME or caspase-8/GSDMD cascades.

Figure 3

The distribution of macrophage populations in the lung. Macrophages in the lungs are composed of Alveolar macrophages (AMs) and interstitial macrophages (IMs). AMs are located in the alveoli, and IMs reside in the parenchyma between the microvascular endothelium and alveolar epithelium. When there is pulmonary inflammation and injury, circulating monocytes in capillaries are subsequently recruited to the lungs and converted into AM-like cells.