Can we treat inflammation by managing misbehaving monocytes?

Summary

When monocytes migrate from blood into tissues they differentiate into macrophage‐like cells. The outcome of this differentiation process is strongly influenced by the tissue environment, and the macrophages produced help control the immunological properties of the tissue. The process of monocyte–macrophage differentiation is therefore potentially attractive when seeking therapeutic targets to amplify or modulate the inflammatory response. Here we highlight recent research in this area, identifying the gene Paqr11 as an important factor in monocyte differentiation, and therefore an important potential target for reducing macrophage‐mediated inflammation in arthritis.

It is important to understand the relationships between mononuclear phagocytes (MNPs) and the factors that control their functions, because they play pivotal roles in both responding to, and in controlling immune responses in tissues. The behaviour of MNPs has a huge effect on both the stromal and the adaptive immune compartments; it strongly influences the outcome of responses to pathogens and inflammatory stimuli. Our understanding of the ontogeny of MNPs has been transformed over the last few years by the work of talented investigators using transgenic animals and high dimensional analyses to decipher the complex relationships between phenotypically similar populations of MNPs [1]. These developments have been mirrored by exciting new insights into human MNP populations, revealing not only broadly similar biology, but also important and interesting differences [2]. An important aim of this field is to identify ways in which these cells can be manipulated, perhaps to improve responses to vaccination, or to reduce the damage caused by unwanted inflammation [3].

When monocytes migrate from blood into peripheral tissues, they undergo a process of differentiation. These differentiating monocytes display a high degree of plasticity, so the outcome of this process is highly dependent on the molecular composition of the micro‐environment in which it occurs. The resulting monocyte‐derived cells can adopt phenotypes outwardly resembling certain types of dendritic cells, or features reminiscent of true embryonically derived macrophages. Historically, and to this day, these monocyte‐derived cells are still often described as ‘macrophages’, despite their clear monocytic origin.

Much has been written about the differentiation of monocytes and the factors that control it, including some high‐quality articles in Immunology. For example, monocytes from human blood can be purified and cultured relatively easily, to enable examination of how specific factors influence their development. Nielson et al. [4] demonstrated that careful attention needs to be paid to the methods used to prepare these cells; different purification approaches can dramatically influence the outcome of the subsequent experiments. Also, in vivo, monocyte‐derived macrophages are critically important in responses to many types of infections, including the globally important responses to infections with parasitic helminths. Over evolutionary time, helminths have developed the ability to influence macrophage functions, including their metabolic functions, in order to inhibit the anti‐helminth immune response [5].

In addition to the examples above, it is becoming clear that macrophages play important roles in the pathogenesis of autoimmune disease. They have, for instance, recently been demonstrated to play critical roles in controlling the switch between inflammatory responses and resolution in rheumatoid arthritis [6]. Here we highlight a recently published paper in Immunology that describes a new role for the molecule PAQR11 in the differentiation of monocytes as they enter the inflamed rheumatoid synovium [7]. The gene was initially identified by mRNA differential display as being expressed in macrophages, but not in freshly isolated monocytes [8], and has previously been described as a Golgi‐localized regulator of Ras signalling [9], and as an important factor involved in the reorganization of the Golgi apparatus during metastatic transformation of tumour cells [10]. The gene is expressed in human synovial macrophages [11]. Here, Lin et al. [7] report that the Paqr11 gene is expressed at high levels during monocyte differentiation and that Paqr11 knockdown leads to apoptosis of monocytes in vitro. Furthermore, in the collagen‐induced arthritis mouse model of arthritis, Paqr11‐deficient mice displayed fewer signs of arthritis and less histological inflammation [7]. The authors conclude, therefore, that targeting monocyte–macrophage differentiation through PARQ11 may be a productive strategy for treating inflammatory arthritis and other autoimmune diseases. Given the plasticity of recruited monocytes, and their importance in controlling both inflammatory and homeostatic processes, further research focussed on identifying the specific molecules that control this differentiation process certainly appears warranted.