Activation of Both TLR and NOD Signaling Confers Host Innate Immunity-Mediated Protection Against Microbial Infection.

Huiting Zhou,Andrew P Coveney,Zhenjiang Bai,D Peter O'Leary,Yiping Li,H Paul Redmond,Jian Wang,Jiang Huai Wang,Ming Wu,He Zhao,Siobhan Blankson,Jie Huang

doi:10.3389/fimmu.2018.03082

Huiting Zhou, Andrew P Coveney + Show 10 more

Open Access

https://doi.org/10.3389/fimmu.2018.03082

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Abstract

The detection of microbial pathogens relies on the recognition of highly conserved microbial structures by the membrane sensor Toll-like receptors (TLRs) and cytosolic sensor NOD-like receptors (NLRs). Upon detection, these sensors trigger innate immune responses to eradicate the invaded microbial pathogens. However, it is unclear whether TLR and NOD signaling are both critical for innate immunity to initiate inflammatory and antimicrobial responses against microbial infection. Here we report that activation of both TLR and NOD signaling resulted in an augmented inflammatory response and the crosstalk between TLR and NOD led to an amplified downstream NF-κB activation with increased nuclear transactivation of p65 at both TNF-α and IL-6 promoters. Furthermore, co-stimulation of macrophages with TLR and NOD agonists maximized antimicrobial activity with accelerated phagosome maturation. Importantly, administration of both TLR and NOD agonists protected mice against polymicrobial sepsis-associated lethality with increased serum levels of inflammatory cytokines and accelerated clearance of bacteria from the circulation and visceral organs. These results demonstrate that activation of both TLR and NOD signaling synergizes to induce efficient inflammatory and antimicrobial responses, thus conferring protection against microbial infection.

Highlights

Innate immunity constitutes the primary defense system of host against invading microbial pathogens [1]
These results indicate that activation of both Toll-like receptors (TLRs) and nucleotidebinding oligomerization domain (NOD) signaling in macrophages leads to an augmented inflammatory response
The individual importance of the membrane-bound TLR2/4 and the cytosolic NOD1/2 during microbial infection has been well documented [6, 9, 22, 23, 29, 34]; it is largely undefined whether TLR and NOD signaling are both critical for host defense to induce an efficient innate immune response, thereby facilitating the host to eradicate the invaded microbial pathogens

Summary

Introduction

Innate immunity constitutes the primary defense system of host against invading microbial pathogens [1]. Detection of PAMPs by PRRs leads to the activation of intracellular signal transduction pathways, which in turn results in the initiation of inflammatory response and antimicrobial activity, culminating in the elimination of the invaded microbial pathogens [1, 3]. The two principal classes of PRRs predominantly involved in the recognition of molecular structures unique to microbial pathogens are Toll-like receptors (TLRs) and the nucleotidebinding oligomerization domain (NOD)-like receptors (NLRs) [3, 5]. Upon bacterial ligand recognition and binding, both NOD1 and NOD2 recruit the adaptor protein, receptor-interacting protein 2 (RIP2), via homophilic CARD-CARD interactions, thereby activating downstream signal transduction pathways of nuclear factor-κB (NF-κB) and mitogen-activated protein kinase (MAPK), initiating transcription of the targeted genes and necessitating the production of inflammatory cytokines and chemokines, antimicrobial peptides, and type I interferons (IFNs) [12, 20]

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