Origin Of Tissue-resident Macrophages Research Articles

New insights into macrophage heterogeneity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a prototypic autoimmune disease that primarily affects joints. Clinical studies and animal models evidenced that mononuclear phagocytes including monocytes and macrophages are crucial to RA pathogenesis, contributing to inflammation and destruction of cartilage and bone. The last decade of research has tremendously changed our view on the origin of tissue-resident macrophages. In light of the recent publications that reveal important phenotypic and functional heterogeneity among macrophages, it is of paramount importance to identify the synovial macrophage subsets that might amplify the inflammatory response or promote the restoration of tissue homeostasis.In this review, we highlight latest studies applying single-cell RNA sequencing that provide deeper insights in macrophage subsets and their putative functions within both human and mouse synovial joint tissue.

The origins and homeostasis of monocytes and tissue-resident macrophages in physiological situation.

Monocytes and macrophages are critical effectors and regulators of innate immune response. They not only play crucial and distinctive roles in homeostasis, but also contribute to some pathologic processes. The heterogeneity of the macrophage lineage has been widely recognized and, in part, is a result of the specialization of resident macrophages in particular tissue microenvironments. Monocytes are usually known to originate in the bone marrow from a common myeloid progenitor that is shared with neutrophils, and they are then released into the peripheral blood. However, the origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. During embryonic organogenesis, macrophages derived from yolk sac and fetal liver precursors are seeded throughout tissues, persisting in the adulthood as resident, self-maintaining populations. After birth, bone marrow-derived monocytes can replenish tissue resident macrophages following injury, infection and inflammation. In this review, we will mainly summarize our current understanding on the origin, ontogeny and fates of tissue macrophages and will briefly discuss the molecular regulation of resident macrophage homeostasis in physiological situation.

Fetal monocytes and the origins of tissue-resident macrophages

Tissue-resident macrophages have pivotal functions for tissue defense and homeostasis. Two main discoveries have changed our current understanding of macrophage development: Their embryonic origin and their ability to self-renew throughout the lifespan. It is now well accepted that most tissue-resident macrophages are long-lived cells derived from a transient hematopoietic wave of erythro-myeloid progenitors (EMPs) emerging in the yolk sac. At least two distinct pathways derived from EMPs have been implicated in macrophage development. The first one, c-Myb-independent is giving rise to yolk sac macrophages also called primitive macrophages, and bypassing the classical monocytic intermediates. The second requires c-Myb expression and start once EMPs seed the fetal liver where they generate fetal monocytes. Sequentially, primitive macrophages seed every tissue and will ultimately give rise to microglia in the brain, rapidly isolated by the blood brain barrier, while EMP-derived fetal monocytes infiltrate every other tissues and gradually generate the major pool of adult tissue-resident macrophages by diluting the initial primitive macrophage contribution. A third wave of hematopoietic stem cells (HSC)-derived monocytes is also emerging from the fetal liver to contribute to the long-lived macrophage pool established at birth while the adult hematopoiesis is only starting in the bone marrow. We propose here to review recent insights about the different embryonic hematopoietic programs responsible for the generation of long-lived tissue-resident macrophages and their maintenance after birth.

Deletion of PIKfyve alters alveolar macrophage populations and exacerbates allergic inflammation in mice.

Alveolar macrophages (AMs) are specialized tissue-resident macrophages that orchestrate the immune responses to inhaled pathogens and maintain organ homeostasis of the lung. Dysregulation of AMs is associated with allergic inflammation and asthma. Here, we examined the role of a phosphoinositide kinase PIKfyve in AM development and function. Mice with conditionally deleted PIKfyve in macrophages have altered AM populations. PIKfyve deficiency results in a loss of AKT activation in response to GM-CSF, a cytokine critical for AM development. Upon exposure to house dust mite extract, mutant mice display severe lung inflammation and allergic asthma accompanied by infiltration of eosinophils and lymphoid cells. Moreover, they have defects in production of retinoic acid and fail to support incorporation of Foxp3+ Treg cells in the lung, resulting in exacerbation of lung inflammation. Thus, PIKfyve plays a role in preventing excessive lung inflammation through regulating AM function.

Ontogeny of Tissue-Resident Macrophages.

The origin of tissue-resident macrophages, crucial for homeostasis and immunity, has remained controversial until recently. Originally described as part of the mononuclear phagocyte system, macrophages were long thought to derive solely from adult blood circulating monocytes. However, accumulating evidence now shows that certain macrophage populations are in fact independent from monocyte and even from adult bone marrow hematopoiesis. These tissue-resident macrophages derive from sequential seeding of tissues by two precursors during embryonic development. Primitive macrophages generated in the yolk sac (YS) from early erythro-myeloid progenitors (EMPs), independently of the transcription factor c-Myb and bypassing monocytic intermediates, first give rise to microglia. Later, fetal monocytes, generated from c-Myb+ EMPs that initially seed the fetal liver (FL), then give rise to the majority of other adult macrophages. Thus, hematopoietic stem cell-independent embryonic precursors transiently present in the YS and the FL give rise to long-lasting self-renewing macrophage populations.