Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis

Abstract

Tertiary lymphoid tissue (TLT) is lymphoid tissue that forms in adult life as a result of chronic inflammation in a tissue or organ. TLT has been shown to form in a variety of chronic inflammatory diseases, though it is not clear if and how TLT develops in the inflamed colon during inflammatory bowel disease. Here, we show that TLT develops as newly formed lymphoid tissue in the colon following dextran sulphate sodium induced colitis in C57BL/6 mice, where it can be distinguished from the preexisting colonic patches and solitary intestinal lymphoid tissue. TLT in the inflamed colon develops following the expression of lymphoid tissue-inducing chemokines and adhesion molecules, such as CXCL13 and VCAM-1, respectively, which are produced by stromal organizer cells. Surprisingly, this process of TLT formation was independent of the lymphotoxin signaling pathway, but rather under neuronal control, as we demonstrate that selective surgical ablation of vagus nerve innervation inhibits CXCL13 expression and abrogates TLT formation without affecting colitis. Sympathetic neuron denervation does not affect TLT formation. Hence, we reveal that inflammation in the colon induces the formation of TLT, which is controlled by innervation through the vagus nerve.

Development and Function of Secondary and Tertiary Lymphoid Organs in the Small Intestine and the Colon

“…Also, the B cell follicles that develop in the colon of Ahr-deficient mice have been associated with intestinal pathology, such as the formation of anal prolapse, colonic hyperplasia, and increased inflammation upon intestinal infection (43, 58). There is ample evidence also from other studies in mice and in men that intestinal inflammation is associated with enhanced formation of structured lymphoid tissues (59–66) (summarized in Table 1). Yet, the contribution of these lymphoid organs to the perpetuation or exacerbation of the inflammatory pathology was, in the cases where it was tested, less evident.…”

“…In this regard, the group of Reina Mebius recently reported the de novo formation of lymphoid tissues in the colon of mice treated with DSS (66). Although these structures showed all hallmarks of mature ILF in terms of the presence of B cell follicles, DC, FDC, and a vascular network, they also presented a distinct T cell area.…”

Neuronal control of experimental colitis occurs via sympathetic intestinal innervation

“…We specifically denervated the vagal innervation of the intestine by cutting the celiac branch of the vagus nerve, as described previously . The sympathetic innervation of the intestine was transected at the SMN that is located along the mesenteric artery (described previously by Olivier et al ).…”

“…The selective vagotomy (indicated with number 1) consists of cutting the celiac branch of the vagus nerve as described in Section and in detail by Cailotto et al. and Olivier et al . To achieve a selective sympathectomy, we transected the superior mesenteric nerve (indicated with number 2).…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Neurotrophic factor signalling reinforced production of IL‐22 and modulation of epithelial barrier integrity,67 suggesting that LTi‐like ILC3 may have the unique potential to respond to environmental cues from the enteric nervous system. Indeed, inflammation‐induced tertiary lymphoid tissue formation – which is regulated by ILC3 – requires vagal nerve innervation in the intestine 68. In addition, LTi‐like ILC3 were also found to specifically express Neuropilin‐1, an immunoregulatory factor that is expressed by subsets of regulatory T cells,56, 69, 70 which may indicate additional novel and subset‐restricted roles for LTi‐like ILC3.…”