Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

Abstract

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Intestinal mononuclear phagocytes (MNPs) have a crucial role in maintaining epithelial barrier integrity while controlling pathogen invasion by activating an appropriate immune response. However, in genetically predisposed individuals, uncontrolled immune activation to intestinal flora is thought to underlie the chronic mucosal inflammation that can ultimately result in IBD. Thus, MNPs are involved in fine-tuning mucosal immune system responsiveness and have a critical role in maintaining homeostasis or, potentially, the emergence of IBD. MNPs include monocytes, macrophages and dendritic cells, which are functionally diverse but highly complementary. Despite their crucial role in maintaining intestinal homeostasis, specific functions of human MNP subsets are poorly understood, especially during diseases such as IBD. Here we review the current understanding of MNP ontogeny, as well as the recently identified human intestinal MNP subsets, and discuss their role in health and IBD.

Keywords: crohn's disease; dendritic cells; intestine; macrophages; ulcerative colitis.

Figure 1

Ontogeny and development of MNPs. Except EMP and pDC ontogenies, which are exclusively from mice, most of the data are from humans. Red and green dotted lines represent possible overlaps between compartments. For example, pre-cDCs are present in both bone marrow and blood and cDCs are present in both blood and solid tissues. Black dashed lines represent possible developmental processes still under debate. CDP, common DC progenitor; CLP, common lymphoid progenitor; cMoP, common monocyte progenitor; CMP, common myeloid progenitor; EMP, erythro-myeloid progenitor; GMP, granulocyte-macrophage progenitor; HSC, hematopoietic stem cell; LMPP, lymphoid-primed multipotent progenitor; MDP, macrophage-DC progenitor. See the main text for other acronyms.

Figure 2

Schematic of human intestinal mucosa and submucosa structure. The schematic is an overall representation of intestinal organization. For example, only the small intestine has Peyer's patches while only the colon has both inner and outer mucus layers composed of firm and loose mucus, respectively. In addition, this schematic does not represent the villi or the crypts of the intestinal mucosa. The color coding of macrophage subsets and dendritic cell subsets matches that in Figures 1, 3, 4 and 6 to allow continuity in the Figures. Black dashed lines represent the maturation waterfall of macrophages. Questions marks represent remaining unresolved issues regarding differentiation and function of the Mf4 subset. Red arrows show processes that increase or decrease during IBD. ILF, isolated lymphoid follicle; SED, subepithelial dome.

Figure 3

Gating strategy and phenotypic characteristics of human intestinal mucosa MNP subsets and human mLN cDC subsets. (A) Gating strategy to analyze human intestinal mucosa MNP subsets from lamina propria cells. This example is from ileum of a Crohn's disease patient. Lineage is composed of CD3, CD19, and CD56. (B) Expression level of HLA-DR, CD14, and CD11c on human intestinal MNP subsets. The red arrow indicates the Mf maturation waterfall from Mfl to Mf3. (A,B) Based on reference (75). (C) Expression level of CD11c, SIRPα, CD26, CD103, and XCR1 on human intestinal cDC subsets. (D) Gating strategy to analyze human cDC subsets from mesenteric lymph node cells. This example is from mLN of a ulcerative colitis patient. Lineage is composed of CD3, CD19, and CD56. LP, lamina propria; mLN, mesenteric lymph node.

Figure 4

Schematic overview of human intestinal MNP subsets. Main surface markers to identify human intestinal MNP subsets using the gating strategy in Figure 3. This schematic is not intended to show the ontogenic or developmental relationship between the human intestinal MNP subsets.

Figure 5

Frequency of human intestinal MNP subsets in homeostasis and during IBD. These values do not take in account the number of patients or the standard error of the mean from each study. The dashed lines are only to clarify the difference between the type of tissue and do not represent paired values. (A–D) Frequency of human intestinal MNP subsets in homeostasis. (E–G) Comparison of human intestinal MNP subset frequencies in homeostasis and during IBD. a, active lesion areas; q, quiescent lesion areas. References: (A) (132, 225); (B) (226, 227); (C) (75, 134, 220); (D) (132); (E) (223, 228); (F) (132, 225, 228); (G) (132, 229).

Figure 6

Phenotypic and functional characteristics of human intestinal mucosa Mf subsets during homeostasis. (a–d) Expression level of major surface markers on blood monocytes and intestinal mucosa Mf subsets assessed by flow cytometry (intensity level from blood monocytes to Mf4 subset). (e–g) Functional characteristics of blood monocytes and intestinal mucosa Mf subsets assessed ex vivo (intensity level from blood monocytes to Mf4 subset). (h) Time of replenishment of intestinal mucosa Mf subsets assessed in duodenum-pancreas transplanted patients. n.a, not analyzed.