Dysregulated Hematopoietic Stem and Progenitor Cell Activity Promotes Interleukin-23-Driven Chronic Intestinal Inflammation

Abstract

SummaryIn interleukin-23 (IL-23)-dependent colitis, there is excessive accumulation of short-lived neutrophils and inflammatory monocytes in the intestine. It is unknown whether this reflects changes in mature cell populations or whether the IL-23-driven colitogenic T cell program regulates upstream hematopoietic stem and progenitor cells (HSPC). Here we have shown dysregulation of hematopoiesis in colitis mediated by inflammatory cytokines. First, there was an interferon-gamma-dependent accumulation of proliferating hematopoietic stem cells in the bone marrow and spleen. Second, there was a strong skew toward granulocyte-monocyte progenitor (GMP) production at the expense of erythroid and lymphoid progenitors. Extramedullary hematopoiesis was also evident, and granulocyte macrophage-colony stimulating factor (GM-CSF) blockade reduced the accumulation of splenic and colonic GMPs, resulting in amelioration of colitis. Importantly, transfer of GMPs exacerbated colitis. These data identify HSPCs as a major target of the IL-23-driven inflammatory axis suggesting therapeutic strategies for the treatment of inflammatory bowel disease.

Antibody-Opsonized Bacteria Evoke an Inflammatory Dendritic Cell Phenotype and Polyfunctional Th Cells by Cross-Talk between TLRs and FcRs

“…The altered inflammatory profile was regulated on both transcriptional and posttranscriptional levels, depending on the distinct cytokine. Importantly, release of this distinct inflammatory mediator profile by DCs redirected DC-induced Th1 responses toward induction of polyfunctional Th cells producing both IL-17 and GM-CSF (20). Finally, combined activation of TLRs and FcRs on iDCs induced functional characteristics that were similar to those described for inflammatory DCs (infDCs).…”

“…This suggests that TLR and FcR crosstalk induces polarization into polyfunctional GM-CSF-producing Th17 cells. It was described that RORgt-mediated GM-CSF production was induced by IL-23R signaling (20).…”

“…The continuous activation of both receptor classes can result in unremitting neutrophil recruitment, which contributes to severe tissue damage. More recently, a pathogenic role for (IL-23-driven) GM-CSF was described in chronic inflammatory diseases, because GM-CSF production triggered extramedullary hematopoiesis of granulocyte-monocyte progenitors, resulting in colitis (20). Furthermore, IL-23-dependent secretion of GM-CSF by Th cells was shown to evoke experimental autoimmune encephalomyelitis and sustain neuroinflammation (16).…”

Diabetes Inhibits Gr-1+ Myeloid Cell Maturation viaCebpaDeregulation

“…Colitis models show disrupted hematopoiesis, including alterations in hematopoietic stem and progenitor cell (HSPC) proliferation and myeloid/lymphoid differentiation capacity, and shifts in the relative abundance of specific progenitor cells in the BM (12). Diabetes causes systemic chronic inflammation (37), and T2D was recently shown to induce widespread changes to the BM stem cell niche that diminish numbers of early hematopoietic progenitors and deregulate miRNAs induced during the macrophage inflammatory response (38,39).…”

“…The impact of diabetes on individual Gr-1 + subpopulations is unknown. Chronic inflammation perturbs hematopoiesis, possibly via increased myeloid cell turnover at inflammatory sites and a correspondingly elevated demand (12). Stable intrinsic defects induced in myeloid cells by diabetes prior to wound recruitment promote chronic inflammation and impair healing (5).…”