A New Paradigm for Antimicrobial Host Defense Mediated by a Nitrated Cyclic Nucleotide

Abstract

Nitric oxide (NO), produced by inducible NO synthase (iNOS) during infection, plays a crucial role in host defense mechanisms. Salmonella typhimurium infection in mice is associated with excessive production of NO from iNOS as a host defense response. An important cytoprotective and antimicrobial function of NO is mediated by induction of heme oxygenase (HO)-1. The signaling mechanism of NO-dependent HO-1 induction has remained unclear, however. We recently discovered a nitrated cyclic nucleotide, 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), which is formed via guanine nitration with NO and reactive oxygen species. iNOS-dependent 8-nitro-cGMP formation and HO-1 induction were identified in Salmonella-infected mice. Extensive apoptosis observed with iNOS-deficient macrophages infected with Salmonella was remarkably suppressed via HO-1 induced by 8-nitro-cGMP formed in cells. This cytoprotective signaling appears to be mediated by the reaction of 8-nitro-cGMP with protein sulfhydryls to generate a novel post-translational modification named protein S-guanylation. We also found that 8-nitro-cGMP specifically S-guanylates Keap1, a negative regulator of transcription factor Nrf2, which in turn up-regulates transcription of HO-1. Here, we discuss the unique mechanism of NO-mediated host defense that operates via formation of a novel signaling molecule - 8-nitro-cGMP - during microbial infections.

Cell signaling mediated by nitrated cyclic guanine nucleotide

“…We also found that 8-nitro-cGMP increased the nuclear accumulation of Nrf2 and expression of HO-1 in C6 cells [12]. NO-induced expression of HO-1 reportedly contributes to cell survival in solid tumor models and during bacterial infection [10,[47][48][49]. Therefore, the cytoprotection against oxidative stress that 8-nitro-cGMP confers is associated, at least in part, with increased HO-1 expression.…”

Korean Red Ginseng enhances pneumococcal Δpep27 vaccine efficacy by inhibiting reactive oxygen species production

“…S. pneumoniae releases pneumolysin at the time of infection resulting in the generation of ROS, which are highly reactive and can damage cells [4], [44], [45], [46]. During bacterial infection, inflammatory cytokines and interferons upregulate the production of iNOS [5], [47], which also leads to increased ROS levels [6]. ROS activate ERK signaling by inhibiting the dual-specificity phosphatase and ERK-specific phosphatases which negatively regulate ERK [48], [49].…”

Synthetic peptide octarphin (TPLVTLFK), a selective agonist of nonopioidβ-endorphin receptor, stimulates nitric oxide synthesis in macrophages

“…NO plays a crucial role in innate host defense mechanisms against microbial infection. Regardless of the type of pathogen, whether bacteria, viruses, or fungi, iNOS is induced almost universally during the infection process . iNOS induction is synergistically enhanced by inflammatory cytokines and interferon produced during infection .…”