Lymphotoxin beta receptor signaling limits mucosal damage through driving IL-23 production by epithelial cells

Abstract

The immune mechanisms regulating epithelial cell repair after injury remain poorly defined. We demonstrate here that lymphotoxin beta receptor (LTβR) signaling in intestinal epithelial cells promotes self-repair after mucosal damage. Using a conditional gene-targeted approach, we demonstrate that LTβR signaling in intestinal epithelial cells is essential for epithelial IL-23 production and protection against epithelial injury. We further show that epithelial-derived IL-23 promotes mucosal wound healing by inducing the IL-22-mediated proliferation and survival of epithelial cells and mucus production. Additionally, we identified CD4−CCR6+T-bet−RORγt+ lymphoid tissue inducer cells as the main producers of protective IL-22 after epithelial damage. Thus, our results reveal a novel role for LTβR signaling in epithelial cells in the regulation of intestinal epithelial cell homeostasis to limit mucosal damage.

Interleukin 23 in IBD Pathogenesis

“…IL-1β and TNF-α stimulation induces IL-23p19 production by synoviocytes [6]. LPS stimulation of TLR4 or ligation of agonistic antibody to LTβR in the colon epithelial cell line stimulates IL-23 production [4]. Similarly, colon epithelial cells, in situ, were shown to produce IL-23 in an LTβR-dependent fashion.…”

“…Epithelial cells were also shown to contribute to IL-23 production. These include keratinocytes [3], intestinal epithelial cells [4] and glomerular podocytes (epithelial cells in the Bowman's capsule especially during nephrotoxic serum (NTS) nephritis (NTN)) [5]. Furthermore, human fibroblast-like synoviocytes (ex vivo and in vivo) and human colon subepithelial myofibroblasts were shown to produce IL-23p19 upon IL-1β and TNF-α all of which suggest that non-hematopoietic sources may also contribute to IL-23 production to some extent, given the right stimulation [6,7].…”

Citrobacter rodentium -induced colitis: A robust model to study mucosal immune responses in the gut

“…In fact, epithelial cells produce antibacterial RegIII proteins which are necessary for protection against C. rodentium (Zheng et al, 2008;Gallo and Hooper, 2012;Abt and Pamer, 2014;Mukherjee et al, 2014). Recent studies revealed that coordinated cross-talk between gut epithelial cells, RORγt + ILCs, DCs and macrophages is necessary for mucosal healing, control of commensal microbiota and for generation of effective immune responses against gut pathogens (Kruglov et al, 2013;Belkaid and Hand, 2014;Longman et al, 2014;Macho-Fernandez et al, 2015;Mortha et al, 2014). Therefore, the ability to isolate primary intestinal epithelial cells and lymphoid cells from the gut during infection is key in understanding the molecular mechanisms of immune cellmediated mucosal protection.…”

“…1a and (Satoh-Takayama et al, 2008;Wang et al, 2010)). The protective mechanism by which RORγt + ILCs mediate mucosal protection includes expression of surface heterotrimeric lymphotoxin (LTβ2LTα1) which signals via lymphotoxin beta receptor (LTβR) on DCs, macrophages and epithelial cells to induce production of IL-23 (Wang et al, 2010;Tumanov et al, 2011;Macho-Fernandez et al, 2015). IL-23, in turn, activates IL-23R on ILCs to produce IL-22 which signals via IL-22R on intestinal epithelial cells to drive the expression of antibacterial proteins and promote epithelial barrier integrity and epithelial cell regeneration via a STAT3-dependent mechanism (Sugimoto et al, 2008;Cella et al, 2009;Grivennikov et al, 2009;Pickert et al, 2009).…”

CCR6-CCL20 Axis in IBD: What have we learnt in the past 20 years?

“…The cue for this process is provided by IL-23 produced by the epithelial cells. IL-23 induces IL-22 mediated, cell proliferation and increased mucous secretion by a group of lymphoid tissue inducer cells expressing CCR6 and RORγt [43].…”