Coordinate Regulation of Inflammatory Responses by ILC3 and gp38+ Colonic Stromal Cells During Chronic Intestinal Inflammation.

A dynamic interplay between innate lymphoid and tissue stromal cells governs the development and function of lymphoid organs. Although many of the mechanisms underlying these interactions are now well defined, little is known relating to such pathways in non-lymphoid tissues, particularly in the context of human inflammatory disease. 

Here we examined innate lymphoid cell (ILC) and intestinal stromal cell (iSC) interactions during inflammatory bowel disease (IBD) in humans and mice. We identified subsets of ‘lymphoid like’ iSCs in colonic tissue and found that stable phenotypic inflammatory alterations in a population of gp38⁺ cells accompanied human IBD. Activated gp38⁺ iSCs potentiated IL-12/23 production by myeloid cells in a 3D organotypic intestinal culture model and IL-23-responsive human ILC3s regulated colonic stromal cell activation in vitro, driving the development of gp38⁺ICAM-1^hiVCAM-1^hi cells with enhanced expression of TNF and CSF2. Experimental therapeutic intervention using Remicade® (Infliximab-IFX) partially blocked human iSC activation mediated by ILC3s in vitro. 

We found an elevated frequency of TNFα-producing ILCs during human IBD, and colonic TNFα⁺ ILC3s expanded in an innate murine colitis model, alongside highly proliferative ICAM-1^higp38⁺ iSCs. Depletion of ILCs or therapeutic TNFα-blockade in vivo attenuated several parameters of colonic gp38⁺stromal cell activation, including proliferation, ICAM-1 expression and GM-CSF production.

Whole-tissue transcriptional analysis revealed that an ILC-iSC activation signature accompanied human IBD, correlating with both disease severity and patient IFX responsiveness. Thus, IL-23 responsive ILC3s drive TNFα-dependent gp38⁺ inflammatory stromal cell activation during intestinal inflammation, with such pathways providing potential novel avenues for therapeutic development in human IBD.