Physiology and diseases of tissue-resident macrophages

Abstract

Embryo-derived tissue-resident macrophages are the first representatives of the haematopoietic lineage to emerge in metazoans. In mammals, resident macrophages originate from early yolk sac progenitors and are specified into tissue-specific subsets during organogenesis-establishing stable spatial and functional relationships with specialized tissue cells-and persist in adults. Resident macrophages are an integral part of tissues together with specialized cells: for instance, microglia reside with neurons in brain, osteoclasts reside with osteoblasts in bone, and fat-associated macrophages reside with white adipocytes in adipose tissue. This ancillary cell type, which is developmentally and functionally distinct from haematopoietic stem cell and monocyte-derived macrophages, senses and integrates local and systemic information to provide specialized tissue cells with the growth factors, nutrient recycling and waste removal that are critical for tissue growth, homeostasis and repair. Resident macrophages contribute to organogenesis, promote tissue regeneration following damage and contribute to tissue metabolism and defence against infectious disease. A correlate is that genetic or environment-driven resident macrophage dysfunction is a cause of degenerative, metabolic and possibly inflammatory and tumoural diseases. In this Review, we aim to provide a conceptual outline of our current understanding of macrophage physiology and its importance in human diseases, which may inform and serve the design of future studies.

Fig. 1 |. Macrophage ontogeny and specification.

Cells ofthe primitive haematopoietic lineage are shown in blue, cells of the erythromyeloid progenitor (EMP) lineage are in red and cells of the HSC lineage are in taupe. Arrows indicate the developmental relationships between cells. Macrophage-specific transcription factors and tissue signals are labelled in red and blue, respectively. AGM, aorta– gonad–mesonephros; AM, alveolar macrophage; LPM, large peritoneal macrophage; preMacs, EMP-derived macrophage precursors; RPM, red pulp macrophage.

Fig. 2 |. Sensing repertoire of tissue-resident macrophages and related effector functions.

Macrophages display a wide range of sensors that detect and respond to pathogens, unfit cells, tissue microenvironmental signals and metabolites. Taupe arrows indicate an interaction between a specified signal (taupe text) and a macrophage sensor (black text). ALRs, AIM2-like receptors; CLRs, C-type lectin receptors; NLRs, NOD-like receptors; PPARs, peroxisome proliferator-activated receptors; PR, purinergic receptors; ProS, protein S; PtdSer, phosphatidylserine; RARs, retinoic acid receptors; RLRs, RIG-I-like receptors; TAM, TYRO3, AXL and MERTK; TLRs, Toll-like receptors; VDR, vitamin D receptor.

Fig. 3 |. Physiological roles of macrophages and associated disease processes.

Schematic depicting selected functions of macrophages and diseases associated with impairment of these functions. Black arrows indicate directional flow of molecules from the source to the acceptor cell or the sequence of events in a homeostatic process. ALSP, adult-onset leukoencephalopathy with axonal spheroids and pigmented glia; WAT, white adipose tissue; RBC, red blood cell; COPD, chronic obstructive pulmonary dysfunction