The sympathetic nervous system enhances host immune responses to enteric bacterial pathogens in mice

Abstract

Mucosal immune responses to enteric bacterial infections are highly coordinated processes that orchestrate host protection while minimizing the potential for immune-triggered pathology. In the intestinal tract, bidirectional communication occurs between the nervous and immune systems to affect local immune responses by modulating the activity of resident and recruited immune cells, and indirectly on the supporting stromal cells. These neuroimmune signaling pathways that alter host defense have focused on specialized sensory innervation and the unique neurotransmitters released from them. Although the sympathetic nervous system has been established to induce a tissue-protective phenotype in subpopulations of neuron-associated macrophages in the small intestine, the role of these neurons during enteric bacterial infection was unknown. Using genetic labeling of activated neurons with ArcTRAP, we demonstrate that colonic infection in mice induces activation of the rostral ventrolateral medulla, a major sympathetic center in the brainstem. The importance of peripheral sympathetic neurons was further demonstrated using chemical sympathectomy that significantly increased bacterial burden during Citrobacter rodentium (C. rodentium) infection in mice. Increased bacterial burden was matched by a deficit in host protection due to reduced IFNγ production by colonic CD4 + T-cells. Sympathectomy, however, did not diminish the capacity to differentiate into IFNγ- or IL-17A-producing T-cells in vitro, suggesting that the lack of sympathetic innervation during infection may alter this process in vivo without causing sustained T-cell intrinsic defects. In assessing which receptors could mediate these effects, pharmacological antagonists selective for α-adrenergic receptors (αAR), but not β-adrenergic receptors, increased bacterial burden and reduced colonic IFNγ production. Using isolated cell types from the colon of uninfected and infected mice, we identified the αΑR subtypes expressed on immune and stromal cells, with significant upregulation of these receptors on T-cells during C. rodentium infection. Together these data demonstrate the unique role of the sympathetic nervous system and αAR in mucosal immune responses against enteric bacterial pathogens.