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. 2022 Apr 22;13:878244. doi: 10.3389/fimmu.2022.878244

Figure 4.

Figure 4

Pro-inflammatory and anti-inflammatory host responses to PLY. S. pneumoniae triggers both pro-inflammatory and anti-inflammatory responses depending on interacting host cell type and infection context. Left Panel: In excess, pro-inflammatory actions of PLY enhance tissue damage and promote bacterial spread. In epithelial cells, PLY induces production of pro-inflammatory cytokines and chemokines, promoting neutrophil transmigration and compromising epithelial barrier function. PLY-stimulated neutrophils engage in a wide range of effector functions, including degranulation, reactive oxygen species (ROS) production, and neutrophil extracellular trap (NET) release, many of which propagate inflammatory tissue damage and are associated with severe pathology in the lung. PLY can activate macrophages independently or in conjunction with other co-stimulants to cause the release of pro-inflammatory cytokines and chemokines. Macrophages can also be activated by PLY-dependent inflammasome activation, which in bone marrow-derived macrophages leads to IL-1β -mediated inflammation, and in microglia, pyroptotic cell death. PLY is also a potent inducer of macrophage necroptosis, often leading to acute tissue injury. Right Panel: Anti-inflammatory activities of PLY downregulate immune responses and may aid bacterial evasion. During pneumococcal colonization and early stages of lung infection, PLY suppresses inflammatory cytokine production by airway epithelial cells and enhances recruitment ofT regulatory cells, promoting unchecked bacterial colonization. Internalization of PLY by alveolar macrophages and dendritic cells via the mannose receptor MRC-1, or, in bone marrow derived macrophages, PLY triggered LC3- associated phagocytosis, suppress the production of inflammatory cytokines. To avoid complement­ mediated detection and opsonization, PLY acts as a decoy molecule to sequester complement proteins. Finally, PLY triggers apoptosis in a wide range of cell types, including endothelial cells, neurons, and dendritic cells, allowing for non-inflammatory removal of these cell types.