The monocyte-macrophage axis in the intestine

Macrophages are one of the most abundant leucocytes in the intestinal mucosa where they are essential for maintaining homeostasis. However, they are also implicated in the pathogenesis of disorders such as inflammatory bowel disease (IBD), offering potential targets for novel therapies. Here we discuss the function of intestinal monocytes and macrophages during homeostasis and describe how these populations and their functions change during infection and inflammation. Furthermore, we review the current evidence that the intestinal macrophage pool requires continual renewal from circulating blood monocytes, unlike most other tissue macrophages which appear to derive from primitive precursors that subsequently self-renew

Signal regulatory protein alpha (SIRPα) regulates the homeostasis of CD103⁺CD11b⁺ DCs in the intestinal lamina propria

Signal regulatory protein alpha (SIRP alpha/CD172a) is a conserved transmembrane protein thought to play an inhibitory role in immune function by binding the ubiquitous ligand CD47. SIRP alpha expression has been used to identify dendritic cell subsets across species and here we examined its expression and function on intestinal DCs in mice. Normal mucosa contains four subsets of DCs based on their expression of CD103 and CD11b and three of these express SIRP alpha. However, loss of SIRP alpha signaling in mice leads to a selective reduction in the CD103(+)CD11b(+) subset of DCs in the small intestine, colon, and amongmigratory DCs in the mesenteric lymph node. In parallel, these mice have reduced numbers of T(H)17 cells in steady-state intestinal mucosa, and a defective T(H)17 response to Citrobacter infection. Identical results were obtained in CD47KO mice. DC precursors from SIRP alpha mutant mice had an enhanced ability to generate CD103(+)CD11b(+) DCs in vivo, but CD103(+)CD11b(+) DCs from mutant mice were more prone to die by apoptosis. These data show a previously unappreciated and crucial role for SIRP alpha in the homeostasis of CD103(+)CD11b(+) DCs in the intestine, as well as providing further evidence that this subset of DCs is critical for the development of mucosal T(H)17 responses

CD207+ CD103+ dermal dendritic cells cross-present keratinocyte-derived antigens irrespective of the presence of Langerhans cells

Recent studies have challenged the view that Langerhans cells (LCs) constitute the exclusive antigen-presenting cells of the skin and suggest that the dermal dendritic cell (DDC) network is exceedingly complex. Using knockin mice to track and ablate DCs expressing langerin (CD207), we discovered that the dermis contains five distinct DC subsets and identified their migratory counterparts in draining lymph nodes. Based on this refined classification, we demonstrated that the quantitatively minor CD207+ CD103+ DDC subset is endowed with the unique capability of cross-presenting antigens expressed by keratinocytes irrespective of the presence of LCs. We further showed that Y-Ae, an antibody that is widely used to monitor the formation of complexes involving I-Ab molecules and a peptide derived from the I-E α chain, recognizes mature skin DCs that express I-Ab molecules in the absence of I-E α. Knowledge of this extra reactivity is important because it could be, and already has been, mistakenly interpreted to support the view that antigen transfer can occur between LCs and DDCs. Collectively, these data revisit the transfer of antigen that occurs between keratinocytes and the five distinguishable skin DC subsets and stress the high degree of functional specialization that exists among them

A hitchhiker's guide to myeloid cell subsets: practical implementation of a novel mononuclear phagocyte classification system

The classification of mononuclear phagocytes as either dendritic cells or macrophages has been mainly based on morphology, the expression of surface markers, and assumed functional specialization. We have recently proposed a novel classification system of mononuclear phagocytes based on their ontogeny. Here, we discuss the practical application of such a classification system through a number of prototypical examples we have encountered while hitchhiking from one subset to another, across species and between steady-state and inflammatory settings. Finally, we discuss the advantages and drawbacks of such a classification system and propose a number of improvements to move from theoretical concepts to concrete guidelines

Dendritic cell subsets in the intestinal lamina propria: ontogeny and function

The intestinal mucosa is exposed to large amounts of foreign antigen (Ag) derived from commensal bacteria, dietary Ags, and intestinal pathogens. Dendritic cells (DCs) are believed to be involved in the induction of tolerance to harmless Ags and in mounting protective immune responses to pathogens and, as such, to play key roles in regulating intestinal immune homeostasis. The characterization of classical DCs (cDCs) in the intestinal lamina propria has been under intense investigation in recent years but the use of markers (including CD11c, CD11b, MHC class II), which are also expressed by intestinal MΦs, has led to some controversy regarding their definition. Here we review recent studies that help to distinguish cDCs subsets from monocyte-derived cells in the intestinal mucosa. We address the phenotype and ontogeny of these cDC subsets and highlight recent findings indicating that these subsets play distinct roles in the regulation of mucosal immune responses in vivo

Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells

Current systems for conditional gene deletion within mouse macrophage lineages are limited by ectopic activity or low efficiency. In this study, we generated a Mafb-driven Cre strain to determine whether any dendritic cells (DCs) identified by Zbtb46-GFP expression originate from a Mafb-expressing population. Lineage tracing distinguished macrophages from classical DCs, neutrophils, and B cells in all organs examined. At steady state, Langerhans cells (LCs) were lineage traced but also expressed Zbtb46-GFP, a phenotype not observed in any other population. After exposure to house dust mite antigen, Zbtb46-negative CD64(+) inflammatory cells infiltrating the lung were substantially lineage traced, but Zbtb46-positive CD64(−) cells were not. These results provide new evidence for the unique identity of LCs and challenge the notion that some inflammatory cells are a population of monocyte-derived DCs

Human dermal CD14⁺ cells are a transient population of monocyte-derived macrophages.

Dendritic cells (DCs), monocytes, and macrophages are leukocytes with critical roles in immunity and tolerance. The DC network is evolutionarily conserved; the homologs of human tissue CD141(hi)XCR1⁺ CLEC9A⁺ DCs and CD1c⁺ DCs are murine CD103⁺ DCs and CD64⁻ CD11b⁺ DCs. In addition, human tissues also contain CD14⁺ cells, currently designated as DCs, with an as-yet unknown murine counterpart. Here we have demonstrated that human dermal CD14⁺ cells are a tissue-resident population of monocyte-derived macrophages with a short half-life of <6 days. The decline and reconstitution kinetics of human blood CD14⁺ monocytes and dermal CD14⁺ cells in vivo supported their precursor-progeny relationship. The murine homologs of human dermal CD14⁺ cells are CD11b⁺ CD64⁺ monocyte-derived macrophages. Human and mouse monocytes and macrophages were defined by highly conserved gene transcripts, which were distinct from DCs. The demonstration of monocyte-derived macrophages in the steady state in human tissue supports a conserved organization of human and mouse mononuclear phagocyte system

Developmental origin and maintenance of distinct testicular macrophage populations

International audienceTesticular macrophages (tM phi) are the principal immune cells of the mammalian testis. Beyond classical immune functions, they have been shown to be important for organogenesis, spermatogenesis, and male hormone production. In the adult testis, two different macrophage populations have been identified based on their distinct tissue localization and morphology, but their developmental origin and mode of homeostatic maintenance are unknown. In this study, we use genetic lineage-tracing models and adoptive transfer protocols to address this question. We show that embryonic progenitors give rise to the interstitial macrophage population, whereas peritubular macrophages are exclusively seeded postnatally in the prepuberty period from bone marrow (BM)-derived progenitors. As the proliferative capacity of interstitial macrophages declines, BM progenitors also contribute to this population. Once established, both the peritubular and interstitial macrophage populations exhibit a long life span and a low turnover in the steady state. Our observations identify distinct developmental pathways for two different tM phi populations that have important implications for the further dissection of their distinct roles in organ homeostasis and testicular function

Peritoneal macrophage heterogeneity is associated with different peritoneal dialysis outcomes

Peritonitis remains the major obstacle for the maintenance of long-term peritoneal dialysis and dysregulated host peritoneal immune responses may compromise local anti-infectious defense, leading to treatment failure. Whilst, tissue mononuclear phagocytes, comprising macrophages and dendritic cells, are central to a host response to pathogens and the development of adaptive immune responses, they are poorly characterized in the human peritoneum. Combining flow cytometry with global transcriptome analysis, the phenotypic features and lineage identity of the major CD14+ macrophage and CD1c+ dendritic cell subsets in dialysis effluent were defined. Their functional specialization was reflected in cytokine generation, phagocytosis, and antigen processing/presentation. By analyzing acute bacterial peritonitis, stable (infection-free) and new-starter patients receiving peritoneal dialysis, we identified a skewed distribution of macrophage to dendritic cell subsets (increasing ratio) that associated with adverse peritonitis outcomes, history of multiple peritonitis episodes, and early catheter failure, respectively. Intriguingly, we also noted significant alterations of macrophage heterogeneity, indicative of different maturation and activation states that were associated with different peritoneal dialysis outcomes. Thus, our studies delineate peritoneal dendritic cells from macrophages within dialysate, and define cellular characteristics associated with peritoneal dialysis treatment failure. These are the first steps to unravelling the detrimental adaptive immune responses occurring as a consequence of peritonitis

GM-CSF Mouse Bone Marrow Cultures Comprise a Heterogeneous Population of CD11c+MHCII+ Macrophages and Dendritic Cells

SummaryDendritic cells (DCs) are key players in the immune system. Much of their biology has been elucidated via culture systems in which hematopoietic precursors differentiate into DCs under the aegis of cytokines. A widely used protocol involves the culture of murine bone marrow (BM) cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) to generate BM-derived DCs (BMDCs). BMDCs express CD11c and MHC class II (MHCII) molecules and share with DCs isolated from tissues the ability to present exogenous antigens to T cells and to respond to microbial stimuli by undergoing maturation. We demonstrate that CD11c+MHCII+ BMDCs are in fact a heterogeneous group of cells that comprises conventional DCs and monocyte-derived macrophages. DCs and macrophages in GM-CSF cultures both undergo maturation upon stimulation with lipopolysaccharide but respond differentially to the stimulus and remain separable entities. These results have important implications for the interpretation of a vast array of data obtained with DC culture systems