Nociceptive Sensory Neurons Mediate Inflammation Induced by Bacillus Anthracis Edema Toxin.

Nicole J Yang,Liwen Deng,Dylan V Neel,Angela Kennedy-Curran,Michelle Heyang,Isaac M Chiu,Jin Mo Park,Victoria S Tong

doi:10.3389/fimmu.2021.642373

Nicole J Yang, Liwen Deng + Show 6 more

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https://doi.org/10.3389/fimmu.2021.642373

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Abstract

Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen defense. Bacillus anthracis Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood. Here, we find that nociceptive neurons play a role in ET-induced edema and inflammation in mice. Subcutaneous footpad infection of B. anthracis Sterne caused ET-dependent local mechanical allodynia, paw swelling and body weight gain. Subcutaneous administration of ET induced paw swelling and vascular leakage, the early phases of which were attenuated in the absence of Trpv1+ or Nav1.8+ nociceptive neurons. Nociceptive neurons express the anthrax toxin receptor ANTXR2, but this did not mediate ET-induced edema. ET induced local cytokine expression and neutrophil recruitment, which were dependent in part on Trpv1+ nociceptive neurons. Ablation of Trpv1+ or Nav1.8+ nociceptive neurons also attenuated early increases in paw swelling and body weight gain during live B. anthracis infection. Our findings indicate that nociceptive neurons play an active role in inflammation caused by B. anthracis and Edema Toxin to potentially influence bacterial pathogenesis.

Highlights

Nociceptive sensory neurons densely innervate barrier tissues such as the skin, lung and gut, and detect physical and chemical stimuli that are potentially damaging, which initiates pain signaling
To determine whether nociceptive neurons play a role during B. anthracis infection, we utilized a subcutaneous infection model in the footpad of C57BL/6 mice
While we cannot completely rule out potential contributions from vagal sensory neurons, our results indicate that Trpv1+ dorsal root ganglia (DRG) neurons play a significant role in regulating paw swelling and body weight during B. anthracis infection

Summary

Introduction

Nociceptive sensory neurons densely innervate barrier tissues such as the skin, lung and gut, and detect physical and chemical stimuli that are potentially damaging, which initiates pain signaling. Recent work has shown that nociceptive neurons can detect bacterial products and respond by secreting neuropeptides and initiating pain behavior [1,2,3]. Nociceptor activation triggers neurogenic inflammation, an axonal reflex that leads to rapid release of neural mediators from peripheral nerve terminals that in turn act on the vasculature and immune system to drive tissue inflammation [4]. Major nociceptive neuron mediators include the neuropeptides calcitonin generelated peptide (CGRP) and substance P (SP). CGRP acts on vascular smooth muscle cells to promote vasodilation and SP acts on vascular endothelial cells to increase vascular permeability, leading to edema [4].

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