Regulation ofStaphylococcus aureusInfection of Macrophages by CD44, Reactive Oxygen Species, and Acid Sphingomyelinase

Abstract

We showed that CD44 activation by S. aureus stimulated Asm via the formation of reactive oxygen species, resulting in ceramide release, clustering of CD44 in ceramide-enriched membrane platforms, CD44/Asm-dependent activation of Rho family GTPases, translocation of phospho-ezrin/radixin/moesin to the plasma-membrane, and a rapid rearrangement of the actin cytoskeleton with cortical actin polymerization. Genetic deficiency of CD44 or Asm abrogated these signaling events and thereby reduced internalization of S. aureus into macrophages by 60-80%. Asm-deficient macrophages also exhibited reduced fusion of phagosomes with lysosomes, which prevented intracellular killing of S. aureus in macrophages and thereby allowed internalized S. aureus to replicate and cause severe pneumonia. Innovation and Conclusion: The CD44-Asm-ceramide system plays an important role in the infection of macrophages with S. aureus. Antioxid. Redox Signal. 00, 000-000.

Crosstalk Between Acid Sphingomyelinase and Inflammasome Signaling and Their Emerging Roles in Tissue Injury and Fibrosis

“…Ceramide has previously been shown to induce lysosomal activation of cathepsin B, which is related to endoplasmic reticulum stress, autophagy, and apoptosis (Taniguchi et al, 2015;Liu et al, 2016). There might be two possible mechanisms involving ASM and α-toxin induced cathepsin B activation: first, ceramide can directly interact with cathepsin; second, fusion of S. aureus contained phagosomes with acidified lysosomes (Li et al, 2017) possibly makes α-toxin induce lysosome permeabilization and promote the translocation of cathepsins. Notably, leakage of LPS from bacteria invaded phagolysosomes or cytosolic gram-negative bacteria may activate a non-canonical NLRP3 inflammasome (Kayagaki et al, 2013).…”

Ceramide and Regulation of Vascular Tone

“…The ability of ROS to activate different ceramide generating pathways has been extensively studied in many cell types [52,53,54,55]. Thus, a number of reports have indicated that the generation of ROS in response to various stimuli such as antileukemic agents [56], stress [57], ischemia-reperfusion [58], pathogens [59], or hypoxia [26,27] may lead to ceramide accumulation. Both nSMase and aSMase are redox-sensitive enzymes whose activities are incremented by ROS [51,53,55].…”

Sphingolipids role in the regulation of inflammatory response: From leukocyte biology to bacterial infection

“…These events trigger activation of ASMase with formation of Cer‐enriched platform, which induces recruitment and further activation of CD44. This positive feedback loop induces a downstream signaling cascade resulting in recruitment of ERM complex at PM that, in turn, mediates bacterial internalization and killing …”