Interkeukin-34, a cytokine crucial for the differentiation and maintenance of tissue resident macrophages and Langerhans cells

Abstract

IL-34 is a recently discovered cytokine that acts on tissue resident macrophages and Langerhans cells upon binding the receptor for CSF-1, CSF-1R. The existence of two ligands for CSF-1R, IL-34, and CSF-1, raises several intriguing questions. Are IL-34 and CSF-1 redundant or does each perform temporally and spatially distinct functions? Is IL-34 involved in human pathology? Would therapeutic strategies based on selective inhibition or administration of either IL-34 or CSF-1 be advantageous for preventing human pathology? Recent in vivo studies indicate that IL-34 promotes the development, survival, and function of microglia and Langerhans cells; therefore, this cytokine may predominately function in brain and skin biology. Here, we review the evidence for IL-34 as a key cytokine in the development and function of these two diverse cell types and discuss its potential role in pathological conditions.

Keywords: CSF-1; IL-34; Langerhans cell; M-CSF; Macrophage; Microglia; Osteoclast.

Figure 1

Origins of tissue macrophages and impact of IL-34 and CSF-1 on their development. (A) In steady state, most tissue macrophages are derived from precursors that arise from yolk sac or fetal liver and that seed the developing tissues during embryonic development. They have the capacity of self-renewal to maintain homeostasis throughout life. IL-34 and/or CSF-1 have a crucial role in homeostasis, depending on the tissue. On the other hand, blood monocytes are derived from macrophage/DC precursors (MDPs) that reside in the bone marrow. Upon inflammation, inflammatory monocytes (Ly6C^hi) are recruited into inflamed tissues and differentiate into macrophages. (B) Generation of bone-absorbing osteoclasts largely depends on CSF-1 and receptor activator of nuclear factor-κB ligand (RANKL). In Csf1^op/op mice, IL-34 maintains a pool of splenic osteoclast precursors that rescue the osteoporotic phenotype later in life.