Cyclooxygenase-2 Inhibition Reduces Autophagy of Macrophages Enhancing Extraintestinal Pathogenic Escherichia coli Infection

Abstract

Extraintestinal pathogenic Escherichia coli (ExPEC) is one of the top pathogens responsible for bloodstream infection and severe, often fatal, sepsis. Although the virulence factors and host immune responses to ExPEC infection have been investigated, the responses to a particular ExPEC strain could be very different. In this study, we investigated the mechanisms of Cyclooxygenase-2 (COX-2) upregulation in influencing the host defenses against infection of ExPEC XM O2:K1:H7. Our results demonstrated that ExPEC XM O2:K1:H7 infection in mouse and RAW264.7 macrophages leads to COX-2 up-regulation, and COX-2 inhibition significantly enhances ExPEC infection. The up-regulation of COX-2 in macrophages was mediated by Tolllike receptor 4 (TLR4) through the activation of p38 and extracellular signal-regulated kinase/Mitogen-activated protein kinase (ERK/MAPK) pathways. Further studies showed that COX-2 inhibition significantly decreased autophagy in macrophages during ExPEC XM O2:K1:H7 infection. Autophagy inhibition significantly enhanced, while induction reduced ExPEC XM O2:K1:H7 survival in macrophages. In addition, COX-2 inhibition significantly increased macrophage cell death during ExPEC XM O2:K1:H7 infection and increased the expression of anti-inflammatory cytokine interleukin-10 (IL-10). Our results indicate that COX-2 up-regulation benefits host defense against ExPEC XM O2:K1:H7 infection by increasing autophagy in macrophages and by reducing IL-10 expression and macrophage cell death during ExPEC infection.

Proteomics Investigation of the Time Course Responses of RAW264.7 Macrophages to Infections With the Wild-Type and Twin-Arginine Translocation Mutant Strains of Brucella melitensis

“…After synthesis, PGs are secreted from macrophage cells and function as autocrine agents to regulate macrophage functions, including the production of proinflammatory cytokines and NO (Shi et al, 2009). The induction of NO and COX-2 in macrophages by pathogenic microbes and the roles of these regulatory molecules in controlling microbial infection are well documented (Loṕez-Urrutia et al, 2000;Bowman and Bost, 2004;Bernard and Gallo, 2010;Ren et al, 2020). Notably, the ability of Tat-mutant Brucella to resist nitrite in vitro was significantly lower than that of the wild-type strain (Figure 6A).…”

Oral StreptococciS. anginosusandS. mitisinduce distinct morphological, inflammatory, and metabolic signatures in macrophages

“…Inducible nitric oxide synthase (iNOS) leads to the production of nitric oxide (NO), which acts as a signaling molecule to mediate diverse immune response and Cyclooxygenase 2 (Cox2), an inducible enzyme responds to inflammatory mediators by converting arachidonic acid to prostaglandins, thereby regulating inflammation in reaction to injury and infection. Both iNOs and Cox2 are associated with proinflammatory M1 macrophage with a potential to facilitate pathogen killing (42,43). During inflammation, the up-regulation of the inflammatory mediators, including iNOS and COX-2, is controlled by the proinflammatory transcription factor nuclear factor-κB (NF-kB).…”

Novel pyrrolopyrimidine derivatives: design, synthesis, molecular docking, molecular simulations and biological evaluations as antioxidant and anti-inflammatory agents

“…In which the inhibition of PGE synthesis is considered an important anti-inflammatory strategy 93 , 97 , 98 . PGE2 is generated by the conversion of arachidonic acid (AA), which is released and used by 2 different cyclooxygenases (COXs), COX-1 (constitutive) and COX-2 (inducible) 53 , 74 , 88 , 89 , 91 , 99–104 . COX-2 is responsible for prostaglandin production during different pathological processes involving inflammation 97 , 98 , 105 .…”