Tumor Suppressor CYLD Regulates Acute Lung Injury in Lethal Streptococcus pneumoniae Infections

Abstract

Streptococcus pneumoniae (S. pneumoniae) causes high early mortality in pneumococcal pneumonia, which is characterized by acute lung injury (ALI). The molecular mechanisms underlying ALI and the high early mortality remain unknown. Despite recent studies that identify deubiquitinating enzyme cylindromatosis (CYLD) as a key regulator for T cell development, tumor cell proliferation, and NF-kappaB transcription factor signaling, its role in regulating bacteria-induced lethality, however, is unknown. Here, we showed that CYLD deficiency protected mice from S. pneumoniae pneumolysin (PLY)-induced ALI and lethality. CYLD was highly induced by PLY, and it inhibited MKK3-p38 kinase-dependent expression of plasminogen activator inhibitor-1 (PAI-1) in lung, thereby potentiating ALI and mortality. Thus, CYLD is detrimental for host survival, thereby indicating a mechanism underlying the high early mortality of pneumococcal pneumonia.

CCAAT/enhancer-binding protein δ facilitates bacterial dissemination during pneumococcal pneumonia in a platelet-activating factor receptor-dependent manner

“…Bacteria may cross the lung-blood barrier by directly inducing alveolar epithelial cell injury independent of leukocytes (17). To assess the potential role of C/EBPδ in blood-lung barrier integrity associated with S. pneumoniae infection, we evaluated S. pneumoniae-induced Evans blue (EB) dye leakage (18).…”

Synergistic and feedback signaling mechanisms in the regulation of inflammation in respiratory infections

“…58 Interestingly, in response to severe S. pneumoniae infection, CYLD seems to play a critical role in enhancing tissue injury and death in WT mice. 59 This detrimental role of CYLD in acute lung injury during severe S. pneumonia infection is mainly attributed to CYLD's role in negatively regulating the p38 MAPK pathway, leading to the downregulation of type 1 plasminogen activator inhibitor in WT mice, which causes severe tissue injury and alveolar hemorrhaging. 59 Additional deubiquitinases may also play a role in negatively regulating inflammation While CYLD has been well documented in playing a critical role in negatively regulating the host's innate immune response, it is joined by numerous other deubiquitinases that have demonstrated anti-inflammatory roles.…”

A20 and CYLD Do Not Share Significant Overlapping Functions during B Cell Development and Activation

“…The consensus mechanism of these functions is CYLD's specificity for removing K63-linked polyubiquitin chains from substrates, thereby controlling different pathways like NF-kB, MAPK, and Wnt signaling (24)(25)(26)(27)(28). Most of the known molecular targets of CYLD's DUB activity are involved in NF-kB signaling pathways.…”