The ontogeny of synovial tissue macrophages

Abstract

Macrophages are essential components of all body tissues, including the synovium. Tissue macrophages originate either from embryonically seeded "primitive" macrophages or from bone marrow-derived monocytes. In adults, both sources contribute to macrophage populations, with their relative proportions varying across tissues and between steady-state and inflammation. Macrophages are highly responsive to microenvironmental and signalling cues, which significantly influence their function within tissues. This article reviews the current understanding of synovial tissue macrophage ontogeny in health and disease, highlighting knowledge gaps and potential avenues for future research.

Keywords: inflammation; macrophage; ontogeny; osteoclast; synovium.

Figure 1

Distinct ontogenies of resident tissue macrophage populations. (A) During embryogenesis, yolk sac erythromyeloid progenitors (EMPs) give rise to cells that differentiate into long-lived resident tissue macrophages. As gestation progresses, the embryo switches from primitive to definitive haematopoiesis, and the bone marrow eventually takes over as the main source of haematopoiesis. This produces HSC which produce monocytes which can migrate into tissues and form monocyte derived macrophages. (B) Both primitive macrophages and monocyte-derived macrophages contribute to tissue biology and exhibit cell-cell communication with tissue cells. During embryogenesis, prenatal, and postnatal life, tissue development is reliant on primitive macrophages. After birth, homeostasis distinct macrophage subpopulations may have different functions and cell-cell communications with healthy tissue cells to support and maintain tissue function. On ageing or pathological inflammation, this balance is disrupted. This can trigger apoptosis in resident macrophages, increased recruitment of monocyte-derived macrophages, directly damage other cells, and contribute to the dysfunction of the tissue. Modified from Mass et al, 2023 (1). (C) Schematic demonstrating the differing contributions of primitive and definitive haematopoieisis to tissue-resident macrophage populations in murine organs. Modified from Ginhoux and Guilliams, 2016 (2) and Thomas et al, 2023 (10).

Figure 2

The blood-joint barrier and the ontogeny of synovial tissue macrophages. (A) Diagram demonstrating the spatial distribution of synovial tissue macrophages, fenestrated endothelium, and neurons. Left zoom-in demonstrates changing density of different macrophage populations and fenestrated endothelium across XY axis of joint. Right zoom-in demonstrates Z axis of joint, with lining layer formed by MHC-II^neg LYVE1^pos CX3CR1^pos macrophages, with supporting sublayer of lining fibroblasts. MHC2^pos CD11c^neg and MH2^pos CD11c^pos macrophages survey the area around fenestrated capillaries. (B) Primitive macrophages (F4/80^pos, CD11b^neg) contribute to the majority of lining and sublining layer STM during gestation. After birth, there are increasing contributions of monocyte-derived CD11b^pos macrophages to the sublining layer (49). Similar postnatal findings demonstrated using Ms4a3-tdTomato fate-tracker model in Hasegawa et al, 2024 (39). During inflammation in the collagen induced arthritis model (49), embryonic-derived macrophages decline over the course of inflammation, with eventual recovery during resolution. Conversely, the proportion of monocyte-derived macrophages increases in the synovium over the course of inflammation, before waning as the resolution phase progresses.