Macrophage reprogramming for therapy

Abstract

Dysfunction of the immune system underlies a plethora of human diseases, requiring the development of immunomodulatory therapeutic intervention. To date, most strategies employed have been focusing on the modification of T lymphocytes, and although remarkable improvement has been obtained, results often fall short of the intended outcome. Recent cutting-edge technologies have highlighted macrophages as potential targets for disease control. Macrophages play central roles in development, homeostasis and host defence, and their dysfunction and dysregulation have been implicated in the onset and pathogenesis of multiple disorders including cancer, neurodegeneration, autoimmunity and metabolic diseases. Recent advancements have led to a greater understanding of macrophage origin, diversity and function, in both health and disease. Over the last few years, a variety of strategies targeting macrophages have been developed and these open new therapeutic opportunities. Here, we review the progress in macrophage reprogramming in various disorders and discuss the potential implications and challenges for macrophage-targeted approaches in human disease.

Keywords: macrophages; polarization; reprogramming.

Figure 1

Summary of macrophage manipulation techniques for therapeutic purpose. These strategies can directly be applied in vivo, as well as in vitro followed by adaptive transfer of manipulated MФ. Free nucleic acids (1) can be manufactured easily and are very successfully used in some tissues including lungs and skeletal muscle. However, they lack MФ specificity and are rapidly cleared from the environment, mostly by circulating enzymes and kidney. Viral vectors (2) can be employed to deliver nucleic acids, preventing clearance from the system. Depending on the type of vector, gene manipulation can be long term (lentivirus) or transient (adenovirus). Viral vectors are highly efficient and can be modified to improve MФ targeting. However, they do entail safety considerations for patients and manufacturing staff. Free small molecules and cytokines (3) are known to act on MФ polarization. They are easy to administer but prone to degradation. They are also often not MФ specific and can cause off‐target effects and toxicity. Encapsulation of nucleic acids, small molecules and cytokines into nanovectors (4) prolongs their half‐life in the organism, while surface modifications (4b) allow targeting of specific cell types. Antibodies (5) can manipulate MФ polarization by directly binding Fc or other cell surface receptors. While they are generally safe, high doses are often required for therapeutic efficacy translating into high costs