ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation

Abstract

Innate lymphoid cells (ILCs) contribute to host defence and tissue repair but can induce immunopathology. Recent work has revealed tissue-specific roles for ILCs; however, the question of how a small population has large effects on immune homeostasis remains unclear. We identify two mechanisms that ILC3s utilise to exert their effects within intestinal tissue. ILC-driven colitis depends on production of granulocyte macrophage-colony stimulating factor (GM-CSF), which recruits and maintains intestinal inflammatory monocytes. ILCs present in the intestine also enter and exit cryptopatches in a highly dynamic process. During colitis, ILC3s mobilize from cryptopatches, a process that can be inhibited by blocking GM-CSF, and mobilization precedes inflammatory foci elsewhere in the tissue. Together these data identify the IL-23R/GM-CSF axis within ILC3 as a key control point in the accumulation of innate effector cells in the intestine and in the spatio-temporal dynamics of ILCs in the intestinal inflammatory response.DOI: http://dx.doi.org/10.7554/eLife.10066.001

Interleukin 23 in IBD Pathogenesis

“…Similar to adaptive cell-induced colitis models, during anti-CD40-induced colitis ILC3 contributed to GMCSF substantially, and its blockade via neutralizing antibodies blocked colitogenesis [101,102]. GMCSF-dependent recruitment of myeloid effector cells (eosinophils-monocytes) may be the underlining mechanism for the pathogenic effects as described in adaptive cell-induced colitis models [111,112].…”

“…Both human and mouse ILC3s form IBD patient intestine and murine intestine, respectively, were shown to produce GMCSF in an IL-23-dependent manner [101,102]. Similar to adaptive cell-induced colitis models, during anti-CD40-induced colitis ILC3 contributed to GMCSF substantially, and its blockade via neutralizing antibodies blocked colitogenesis [101,102].…”

“…In fact, in naïve T-cell transfer-induced adaptive cell-driven coltitis, anti-CD40 or Hepaticus-induced innate colitis models, IL-23-dependent IFN-γ produced by either Th17 or innate ILC3 cells was shown to play a pathogenic role [38,100]. IFN-γ in this context was shown to regulate myeloid inflammatory cell recruitment (neutrophils, monocytes and eosinophils) to the tissue [60,101,102]. In both CD4 Besides acting as an inflammatory cytokine, IFN-γ was also shown to regulate IEC survival proliferation through Wnt inhibitor Dkk, which ultimately negatively impacts intestinal epithelial barrier function [106,107].…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…However, chronic activation of ILC3 can result in disease due to uncontrolled inflammation. ILC3 drive colitis in an innate anti‐CD40 driven model of colitis and during Helicobacter hepaticus infection in an IL‐23‐dependent manner, which has been associated with production of GM‐CSF and IFN‐ γ by pro‐inflammatory ILC3 71, 118, 128, 129. Neonatal ILC3 can also mediate intestinal pathology in response to transgenic over‐expression of IL‐23 through the release of IL‐17A, IL‐22, IFN‐ γ and GM‐CSF 130.…”

IL-33, IL-25, and TSLP induce a distinct phenotypic and activation profile in human type 2 innate lymphoid cells

“…ECs are an attractive therapeutic target in several inflammatory diseases, and understanding the relative role that ECs play in modulating ILC behavior is critical, especially because ILCs are emerging as key players in directing other cell types, such as dendritic cells, T cells, and even B cells, [13][14][15] in such settings. Here, we show a differential role for TSLP in cell survival but a critical role for IL-33 in effector function, particularly in combination with other ECs or IL-2.…”