Fig 5. Cascade of caspase activation and potential pathways influenced by Ureaplasma spp.

Simplified scheme (a) depicting caspase activation processes. Multiple trigger factors can initiate apoptosis and pyroptosis. Under engagement of several additional proteins not mentioned here, initiator caspases 4 and 5 for pyroptosis or 8 and 9 for apoptosis are produced and activated. These subsequently activate effector caspases 1 or 3. Caspases are activated by cleavage or dimerization, often followed by a maturational process. Control mechanisms confine programmed cell death [26, 27, 43–45]. The potential influence of Ureaplasma spp. on apoptosis according to our results is illustrated in (b). Pathways affected by Ureaplasma isolates are marked in red. In A549 cells, Ureaplasma-triggered reduction of caspase 8 and 9 mRNA may result in an absent increase in protein production and active caspases. Ultimately, effector caspase 3 remains unactivated and apoptosis is impaired. In HPMEC, Ureaplasma spp. seem to enhance caspase 8 protein and caspase 9 activity. Both caspases may subsequently activate effector caspase 3 and induce apoptosis. It remains to be determined if the caspase 3 activation observed is directly due to Ureaplasma or a consequence of initiator caspase activation. Hypothesized underlying mechanisms Ureaplasma isolates may engage are indicated with a dashed line. Ⱶ inhibit / down-regulate; ← activate / up-regulate. CASP: caspase; IFN: interferon; LPS: lipopolysaccharide; NK: natural killer; TLR: toll-like receptor; TNF: tumor necrosis factor. Illustrations: https://smart.servier.com/.