Monocytes and macrophages are important components of the innate immune system [1]. The innate immune system provides the first defense line against external or internal pathogens and danger signals (e.g., danger associated molecular pattern molecules, DAMPs ), by triggering a protective inflammatory response that normally is self-limiting after clearance of the initial trigger [2]. In addition, an adaptive and longer lasting adaptive and specific immune response may be initiated by the same cells. The innate immune response provided by monocytes and macrophages (but also by other cellular components of the innate immune system) aims to directly destroy pathogens. This is followed by a phase in which the destroyed pathogens such as bacteria as well as cell detritus and damaged extracellular matrix material are taken up (“phagocytosed”) by the cells, degraded and such removed by the same cells to allow tissue repair and recovery of the healthy situation [3].

Besides monocytes and macrophages the mononuclear phagocyte system (MPS ) is composed of lineage-committed bone marrow precursors, circulating monocytes, resident tissue macrophages, and dendritic cells (DC) [1].

Monocytes and macrophages have been shown to play an important role during the initiation and chronification of inflammatory bowel disease (IBD ) [4–6]. They contain many functionally important proteins that carry potential variants known to be associated with the risk for developing IBD. Macrophage differentiation from monocytes occurs in the intestine associated with the acquisition of a typical functional phenotype that is tissue specific depending on microenvironmental signals, such as signal from the gut lumen (e.g., products of the intestinal microbiota) [5, 6]. Obviously a differentiation of monocytes into macrophages in the intestine normally occurs under “non-inflammatory” or “minor inflammatory” conditions. With respect to this a “normal” non-activated monocyte will differentiate into a “normal” intestinal macrophage after entering the mucosa form the blood stream [7, 8]. Under inflammatory conditions such as IBD the differentiation is altered but not completely blocked [9–15]. A different phenotype with most likely different functions will occur [9–15].

The mechanisms how the various risk genes for IBD —and especially the ones that are associated with functions of the innate immune response—influence this process of tissue specific and inflammation-modified macrophage differentiation so far is largely unclear.

Monocytes represent 5–10 % of peripheral blood leukocytes in humans but only 2–4 % of the total leukocytes in mice [1]. Therefore differences in monocyte function are likely and results obtained from mouse experiments may be not easily transferable to the human “monocyte situation.” Circulating monocytes together with lymphocytes morphologically belong to the group of “mononuclear cells” with mainly round but frequently also somewhat irregular cell shape, oval- or kidney-shaped nuclei, and cytoplasmic vesicles. In contrast to lymphocytes monocytes have a high cytoplasm-to-nucleus ratio. Monocytes usually remain in the blood stream and circulate through the blood vessels for 24–48 h and then migrate into tissues or are removed. Before entering the blood stream monocytes originate and differentiate in the bone marrow from hematopoietic stem cells (HSCs) through several sequential differentiation stages such as the common myeloid progenitor (CMP) , the granulocyte-macrophage progenitor (GMP ) as well as the common macrophage and DC precursor (MDP) [1].

Macrophage colony-stimulating factor (M-CSF ) (also known as colony stimulating factor-1, CSF-1) is the most important growth factor and essential component for the differentiation of monocytes/macrophages [1, 16, 17]. Granulocyte-macrophage colony-stimulating factor (GM-CSF) also is involved in the development of monocytes/macrophages especially under inflammatory conditions [1, 16, 17].

Monocytes as important component of the innate immune system initiate inflammatory responses to invading pathogens by killing, neutralizing and removing them via phagocytosis, production of reactive oxygen species (ROS), production of nitric oxide (NO), of myeloperoxidase, and secretion of cytokines and/or chemokines. As mentioned above monocytes can trigger T-cell responses and direct T-cell differentiation (e.g., by secretion of interferon gamma (IFNγ) or IL-12) [4, 18, 19].

Circulating human peripheral blood monocytes are a heterogeneous cell population that can be discriminated by their surface antigen expression [20]. Mainly three functional subsets of human monocytes have been identified. The discrimination of the three subsets is mainly based on two surface antigens: CD14 (part of the LPS receptor) or CD16 (Fcγ RIII) [20]. Up to 90 % of human monocytes display high CD14 but no CD16 surface expression in flow cytometry (FACS) analyses (usually they are annotated as CD14++CD16− or CD14+CD16−). They may be seen as the “classical monocytes” as this population has been described first and also represents the majority of the circulating monocytes. The remaining 10 % of circulating monocytes can be split into two subtypes: A population with high CD14 and low (but not absent in contrast to the “classical” monocytes) CD16 expression (usually annotated as: CD14++CD16+ or CD14+CD16+), and a so called “non-classical subset ” with low CD14 but high CD16 expression (CD14+CD16++ or CD14dimCD16+) [20].

Whether there are significant functional differences between those subpopulations is not completely clear and still a matter of discussion [1, 20]. Differences between these monocyte subpopulations with respect to their capacity to be activated by bacterial products and secrete pro-inflammatory cytokines have been described [1, 20]. This may be obvious as CD14 is part of the LPS receptor complex and subsequently a lower expression may limit the ability to react to LPS exposure. Further differences with respect to antigen presentation, phagocytosis, and oxidative burst have been reported [1, 20]. In a recent review article functional differences between the subsets have been described and discussed in detail [21]. In general, “classical” human monocytes have the ability to induce a pro-inflammatory reaction similar to the murine Ly6C+ monocytes (also termed “inflammatory” monocytes) [1]. In contrast, the “non-classical”, high CD16 expressing monocytes may have properties similar to those of murine Ly6C− monocytes (also termed “alternative” or “patrolling” monocytes) [1]. Whereas classical inflammatory monocytes respond to the chemokine CCL2 as they express the respective receptor triggering recruitment to inflammatory sites the CD16++ monocytes respond to CX3C-chemokine ligand 1 [CX3CL1, the human fractalkine and mouse neurotactin] as chemokine [1].

Resident macrophages are found in virtually all tissues of adult mammals, where they usually represent up to 10–15 % of the total cell number [22–24]. In the intestinal mucosa they are mainly localized in the lamina propria [25]. The specific tissue environment is thought to influence the differentiation of monocytes into the organ or tissue specific macrophage phenotype explaining a significant heterogeneity between macrophages isolated from different organs or tissues [1].

The tissue macrophages found in the gut wall represent one of the largest—if not the largest—compartments of the mononuclear phagocyte system in the body. They are localized preferentially at the sites of antigen entry, e.g., in the periepithelial region of the small intestine and in the subepithelial domes of Peyer’s patches. Macrophages constitute 10–20 % of the mononuclear cells in the lamina propria, as determined by immunohistochemistry and tissue disaggregation experiments [25].

Intestinal macrophages are involved in the pathogenesis of IBD. With respect to their transcriptional profile they differ from macrophages in other tissues such as Kupffer cell in the liver, alveolar macrophages or osteoclasts [26–29]. Intestinal macrophages show a specific phenotype with low expression of typical monocyte antigens such as CD14 or CD16 [13]. The differentiation of intestinal macrophages is partly regulated by epithelial cells as it can be in vitro induced in spheroid cultures of intestinal epithelial cells [7, 8]. They display a more “anergic,” “regulatory,” “tolerogenic,” or M2 phenotype with also low expression of costimulatory molecules such as CD80 or CD86 and low expression of pattern recognition receptors such as TLR4 or TLR2 [12, 30].

The phenotype and the functional characteristics of intestinal macrophages are altered during chronic inflammation in IBD [10–12, 14, 15, 31]. Whether this is only due to a disturbed differentiation of invading monocytes remains to be elucidated and is not clear so far.

During acute flares of IBD the heterogeneity of the intestinal macrophage population is strongly increased. In mouse models of colitis such as the acute DSS colitis model an early influx of monocytes/macrophages into the mucosa is observed [32–34]. There usually is a concomitant “loss” of resident macrophages, due to tissue adherence, emigration, or death. This is also called “macrophages disappearance reaction” and has mainly been described for peritoneal and alveolar macrophages (as it is easier to describe and analyze in those tissues) [35].

Inflammatory macrophages most likely derive from recruited blood monocytes that do not undergo the normal process of differentiation into intestinal macrophages in the mucosa [15, 36].

There are two main chemokines and related receptors found to be responsible for the recruitment of monocytes into the inflamed intestinal mucosa: CCL2/CCR2 and CX3CL1/CX3CR1, respectively [37–39]. CCL2 is produced by mucosal fibroblasts, intestinal epithelial cells as well as endothelial cells in response to the inflammatory environment and in response to invading microbes.

The intestinal mucosa is challenged by a permanent contact to an indeterminable multiplicity of bacterial and food antigens from the intestinal lumen. Mechanisms must exist, which facilitate an immediate immune reaction against pathogens penetrating into the mucosa. On the other hand, ongoing immune reactions against commensal bacteria or food antigens must be effectively prevented—otherwise the consequence is a chronic mucosal inflammation—as we find it in patients with IBD.

In general two major types of macrophages have been described in recent years: M2 macrophages are tolerogenic, promote tissue healing and growth whereas M1 macrophages have easily activated defense functions and kill bacteria as well as initiate inflammation [1]. This is associated with a shift in cell metabolism: In M1 macrophages the arginine metabolism is shifted to NO and citrulline [1]. In contrast in M2 macrophages it is shifted to ornithine and polyamines [1].