Unravelling monocyte functions: from the guardians of health to the regulators of disease

Abstract

Monocytes are a key component of the innate immune system. They undergo intricate developmental processes within the bone marrow, leading to diverse monocyte subsets in the circulation. In a state of healthy homeostasis, monocytes are continuously released into the bloodstream, destined to repopulate specific tissue-resident macrophage pools where they fulfil tissue-specific functions. However, under pathological conditions monocytes adopt various phenotypes to resolve inflammation and return to a healthy physiological state. This review explores the nuanced developmental pathways and functional roles that monocytes perform, shedding light on their significance in both physiological and pathological contexts.

Keywords: cancer; haematopoiesis and metabolic disease; inflammation; macrophages; monocytes.

Graphical Abstract

Figure 1.

Monocyte development. Haematopoiesis begins with a small number of active haematopoietic stem cells (HSC), which populate a reservoir of multipotent progenitors (MPPs); (indicated by the numbers 2–4 [38]) that already exhibit tendencies toward specific cell lineages. As differentiation continues, precursor populations become progressively more restricted towards specific fates and are classified according to their cellular output and surface characteristics into various precursor subsets (depicted by rectangles), which sometimes exhibit a shared overlapping surface marker profile. Note that the majority of classical monocytes derive from granulocyte-monocyte precursors (GMP), while only a small fraction of Ly6C⁺ expressing cells derive from monocyte and dendritic cell progenitors (MDP). Several open questions remain during monocyte development depicted in grey with question marks: (a) Do MDP-derived monocytes go through a common monocyte progenitor (cMoP) stage? (b) What is the relationship between pro-DC3 and MDP-derived monocytes? (c) GMP- and MDP-derived monocytic cells can experimentally loose Ly6C expression, but do both convert into non-classical monocytes under physiological conditions? Further abbreviations: CLP, common lymphoid progenitor; CMP, common myeloid progenitor; MEP, megakaryocyte-erythroid progenitors; DC, dendritic cell; cDC, conventional DC; pDC, plasmacytoid DC. Figure adapted from [38] with permission.

Figure 2.

The sweet shop analogy. A sweet shop in a village (organism) represents an organ or an inflammatory environment (infection, injury, or tumour). Frequent visitors to the shop are children (monocytes) who have an extraordinary ability to consume many of the sweets, representing cytokines and secreted mediators that are available in the shop. Each shop offers a different selection of sweets, from lollipops and liquorice to marshmallows, where the range of sweets mirrors the cytokines and chemokines found in different inflammatory microenvironments. For instance, liquorice represents pro-inflammatory TNFα, lemon sherbet stands for IFNγ, while caramel symbolizes anti-inflammatory IL-4. Yet, there are many other sweets on offer, which can simultaneously be tasted by the children, as long as the shop is open (an indication of ongoing inflammation). Under these circumstances, it is unlikely that the children will only eat caramel (IL-4) or lemon sherbet (IFNγ). They will randomly taste other sweets that are available, depending on the architecture of the sweet shop and the sweets on offer. Accordingly, it is possible that the children eat sour lemon sherbet (IFNγ), sweet caramel (IL-4), and bitter liquorice (TNFα) in immediate succession, which all influence the mood and behaviour of the children, reflecting gene expression changes and functional adaptation of the monocyte-derived cells. It is also possible that one child does not like the taste of a particular sweet (such as bitter liquorice), symbolizing the absence or down-regulation of certain cyto- or chemokine receptors on monocytes. Therefore, the in vitro single stimulus polarization model may be suitable to precisely control the functional outcome of a single mediator. However, it fails to mimic the complex 3D structured in vivo dynamics, the many secreted factors available in a microenvironment, temporal aspects of inflammation, and the array of phenotypes monocyte-derived cells can display during different stages of inflammation, injury, or cancer. Drawing by Maya Rachman.