Stromal Cells Covering Omental Fat-Associated Lymphoid Clusters Trigger Formation of Neutrophil Aggregates to Capture Peritoneal Contaminants

Lucy Helen Jackson-Jones,Peter Smith,Jordan Raymond Portman,Marlène Sophie Magalhaes,Katie Jude Mylonas,Matthieu Marie Vermeren,Mark Nixon,Beth Emily Pollot Henderson,Ross Dobie,Sonja Vermeren,Laura Denby,Neil Cowan Henderson,Damian James Mole,Cécile Bénézech

doi:10.1016/j.immuni.2020.03.011

Abstract

SummaryThe omentum is a visceral adipose tissue rich in fat-associated lymphoid clusters (FALCs) that collects peritoneal contaminants and provides a first layer of immunological defense within the abdomen. Here, we investigated the mechanisms that mediate the capture of peritoneal contaminants during peritonitis. Single-cell RNA sequencing and spatial analysis of omental stromal cells revealed that the surface of FALCs were covered by CXCL1+ mesothelial cells, which we termed FALC cover cells. Blockade of CXCL1 inhibited the recruitment and aggregation of neutrophils at FALCs during zymosan-induced peritonitis. Inhibition of protein arginine deiminase 4, an enzyme important for the release of neutrophil extracellular traps, abolished neutrophil aggregation and the capture of peritoneal contaminants by omental FALCs. Analysis of omental samples from patients with acute appendicitis confirmed neutrophil recruitment and bacterial capture at FALCs. Thus, specialized omental mesothelial cells coordinate the recruitment and aggregation of neutrophils to capture peritoneal contaminants.

Highlights

The omentum, a visceral fat depot contained within a fold of peritoneum, has the capacity to rapidly absorb particles and pathogens present in the peritoneal cavity (Meza-Perez and Randall, 2017; Platell et al, 2000)
Peritonitis induces de novo fat-associated lymphoid clusters (FALCs) formation that is dependent on the production of tumor necrosis factor (TNF) by monocytes and/or macrophages, and TNF receptor (TNFR) signaling in stromal cells (Benezech et al, 2015)
A population of CXCL13+ stromal cells is found around the outside of FALCs (Benezech et al, 2015; Rangel-Moreno et al, 2009)

Summary

Introduction

The omentum, a visceral fat depot contained within a fold of peritoneum, has the capacity to rapidly absorb particles and pathogens present in the peritoneal cavity (Meza-Perez and Randall, 2017; Platell et al, 2000). FALCs support multifaceted stromal-immune cell interactions, which are critical for the maintenance and function of innate-like B cells (IBCs) within the serous cavities, as well as facilitating T-cell-dependent B cell immune responses to peritoneal antigens (Ansel et al, 2002; Benezech et al, 2015; Rangel-Moreno et al, 2009). Serous B cells migrate into FALCs where the provision of interleukin (IL)-5 by type 2 innate lymphocytes (ILC2s) causes rapid B cell proliferation and IgM secretion (JacksonJones and Benezech, 2018; Jackson-Jones et al, 2016). The cross-talk between monocytes and FALC stromal cells supports B cell differentiation (Perez-Shibayama et al, 2018) and FALC expansion (Benezech et al, 2015)

Results

Discussion

Conclusion