Macrophages have a central role in numerous physiological processes, such as immune defense, maintenance of tissue homeostasis, wound healing, and inflammation. Moreover, in numerous severe disorders, such as cancer or chronic inflammation, their functions can be profoundly affected. Macrophages continuously sense their environment and adapt their phenotypes and functions to the local requirements; this process is called plasticity. In addition to stress signals, metabolites, and direct cell‐contact interactions with surrounding cells, numerous cytokines play a central role in controlling macrophage polarization. In this review, we will focus on three human macrophage differentiation factors: macrophage colony‐stimulating factor (M‐CSF), IL‐34, and granulocyte M‐CSF. These CSFs allow human monocyte survival, promote their differentiation into macrophages, and control macrophage polarization as they give rise to cells with different phenotype and functions. Based on recent observations, the role of granulocyte CSF on macrophage polarization is also addressed. Finally, our current knowledge on the expression of these growth factors in tumor microenvironment and their impact on the generation and polarization of tumor‐associated macrophages are summarized.

In physiological conditions, self-DNA released by dying cells is not detected by intracellular DNA sensors. In chronic inflammatory disorders, unabated inflammation has been associated with a break in innate immune tolerance to self-DNA. However, extracellular DNA has to complex with DNA-binding molecules to gain access to intracellular DNA sensors. IL-26 is a member of the IL-10 cytokine family, overexpressed in numerous chronic inflammatory diseases, in which biological activity remains unclear. We demonstrate in this study that IL-26 binds to genomic DNA, mitochondrial DNA, and neutrophil extracellular traps, and shuttles them in the cytosol of human myeloid cells. As a consequence, IL-26 allows extracellular DNA to trigger proinflammatory cytokine secretion by monocytes, in a STING- and inflammasome-dependent manner. Supporting these biological properties, IL-10-based modeling predicts two DNA-binding domains, two amphipathic helices, and an in-plane membrane anchor in IL-26, which are structural features of cationic amphipathic cell-penetrating peptides. In line with these properties, patients with active autoantibody-associated vasculitis, a chronic relapsing autoimmune inflammatory disease associated with extensive cell death, exhibit high levels of both circulating IL-26 and IL-26-DNA complexes. Moreover, in patients with crescentic glomerulonephritis, IL-26 is expressed by renal arterial smooth muscle cells and deposits in necrotizing lesions. Accordingly, human primary smooth cells secrete IL-26 in response to proinflammatory cytokines. In conclusion, IL-26 is a unique cationic protein more similar to a soluble pattern recognition receptor than to conventional cytokines. IL-26 expressed in inflammatory lesions confers proinflammatory properties to DNA released by dying cells, setting up a positive amplification loop between extensive cell death and unabated inflammation.