Reprogramming of Monocytes by GM-CSF Contributes to Regulatory Immune Functions during Intestinal Inflammation

Abstract

Human and murine studies showed that GM-CSF exerts beneficial effects in intestinal inflammation. To explore whether GM-CSF mediates its effects via monocytes, we analyzed effects of GM-CSF on monocytes in vitro and assessed the immunomodulatory potential of GM-CSF–activated monocytes (GMaMs) in vivo. We used microarray technology and functional assays to characterize GMaMs in vitro and used a mouse model of colitis to study GMaM functions in vivo. GM-CSF activates monocytes to increase adherence, migration, chemotaxis, and oxidative burst in vitro, and primes monocyte response to secondary microbial stimuli. In addition, GMaMs accelerate epithelial healing in vitro. Most important, in a mouse model of experimental T cell–induced colitis, GMaMs show therapeutic activity and protect mice from colitis. This is accompanied by increased production of IL-4, IL-10, and IL-13, and decreased production of IFN-γ in lamina propria mononuclear cells in vivo. Confirming this finding, GMaMs attract T cells and shape their differentiation toward Th2 by upregulating IL-4, IL-10, and IL-13 in T cells in vitro. Beneficial effects of GM-CSF in Crohn’s disease may possibly be mediated through reprogramming of monocytes to simultaneously improved bacterial clearance and induction of wound healing, as well as regulation of adaptive immunity to limit excessive inflammation.

Development of a transendothelial shuttle by macrophage modification

“…Noteworthy, the addition of cytokine did not diminish MCP-1 stimulated migration (p = 0.704) compared to AbsBeads group. However, the slight reduction in migration is contradictory to previous reports that presented an exposure to GM-CSF upregulated migration and chemotaxis (Dabritz et al 2015).…”

“…For example, a recent paper claimed increased migration and chemotaxis after treatment with this cytokine (Dabritz et al 2015), which would further promote cell migratory capacity. Additionally, the phagocytic capacity or engulfment capacity of macrophages has been shown to increase after treatment with this cytokine (Eischen et al 1991).…”

Diversity and functions of intestinal mononuclear phagocytes

“…134 Production of GM-CSF and VEGF-C during inflammation may reprogramme the differentiation of monocytes into m that produce reparative mediators such as arginase, prostaglandins and IL-13. 200,201 Thus the overall role of the monocyte-m lineage in intestinal inflammation may reflect a balance between local pathogenic and regulatory mechanisms.…”

Genetic and Transcriptomic Variation Linked to Neutrophil Granulocyte–Macrophage Colony-Stimulating Factor Signaling in Pediatric Crohn’s Disease

“…1,2 We discovered that pediatric and adult CD patients exhibit an acquired basis for neutrophil dysfunction, GM-CSF auto-antibodies (GMAb), which increase in titer with older age and suppress GM-CSF:STAT5 signaling in a cell-extrinsic manner. 3,4 GMAb carriage is associated with reduced neutrophil STAT5 activation, phagocytic capacity, and bacterial killing, and with high rates of antimicrobial serologies (AMS) and stricturing behavior.…”