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. 2021 Jul 16;22(14):7606. doi: 10.3390/ijms22147606

Figure 6.

Figure 6

Simplified schematic of LPS-induced inflammatory pathway. Toll-like receptor 4 (TLR4) recognises and binds lipopolysaccharide (LPS). Binding activates two signal transduction pathways through the stimulation of myeloid differentiation primary response gene 88 (MyD88) and TIR domain-containing adaptor inducing IFN-β (TRIF) adaptor molecules. MyD88 and TRIF activates two transcription factors, nuclear factor-κB (NFκB) and interferon response factors (IRFs). IRFs enhance the expression of Type I interferon genes, resulting in the secretion of type I interferons. NFκB promotes transcription of pro-inflammatory genes, such as cytokines and chemokines, resulting in acute inflammation and initiation of the adaptive immunity. NFκB signalling also induces NOD-, LRR-, and pyrin domain–containing protein 3 (NLRP3) gene expression, essential for inflammasome formation. The NLRP3-inflammasome cleaves and activates caspase-1, which cleaves the inactive precursor pro-IL-1β into its biologically active and secreted form, IL-1β. IL-1β secretion results in enhanced inflammation and immune cell infiltration. Caspase-1 also cleaves and activates Gasdermin D (GSDMD), leading to pore formation in the plasma membrane, triggering pyroptosis and further inflammation. This inflammatory pathway is a key regulator of the inflammation associated with CF.