IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia
Open accessAbstract
The differentiation of bone marrow-derived progenitor cells into monocytes, tissue macrophages and some dendritic cell (DC) subtypes requires the growth factor CSF1 and its receptor, CSF1R. Langerhans cells (LCs) and microglia develop from embryonic myeloid precursor cells that populate the epidermis and central nervous system (CNS) before birth. Notably, LCs and microglia are present in CSF1-deficient mice but absent from CSF1R-deficient mice. Here we investigated whether an alternative CSF1R ligand, interleukin 34 (IL-34), is responsible for this discrepancy. Through the use of IL-34-deficient (Il34(LacZ/LacZ)) reporter mice, we found that keratinocytes and neurons were the main sources of IL-34. Il34(LacZ/LacZ) mice selectively lacked LCs and microglia and responded poorly to skin antigens and viral infection of the CNS. Thus, IL-34 specifically directs the differentiation of myeloid cells in the skin epidermis and CNS.
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Langerhans cells are a unique cell population to the skin organ, where fate-mapping of macrophages demonstrates in situ proliferation to Langerhans cells in the skin during embryonic development.
“Langerhans cells are a unique cell population to the skin organ, where fate‐mapping of macrophages demonstrates in situ proliferation to Langerhans cells in the skin during embryonic development.[ 78 , 79 , 80 , 81 ]”
From Coordinated Development of Immune Cell Populations in Vascularized Skin Organoids from Human Induced Pluripotent Stem Cells (2025) · cites this paper as [80]
The Introduction identifies Langerhans cells as resident cells of the epidermis, and the Results section 'The development of microglia and LCs require IL-34' says their primitive precursors populate the skin before birth and expand around birth (page unavailable). The paper does not report macrophage fate-mapping or demonstrate that macrophages proliferate in situ into Langerhans cells during embryonic development. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTranscriptomic and proteomic analyses of microglial cells suggested a microglial homeostatic signature that is perturbed during aging and under pathological conditions.
“Transcriptomic and proteomic analyses of microglial cells suggested a microglial homeostatic signature that is perturbed during aging and under pathological conditions48.”
From A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease (2017) · cites this paper as [48]
The Results section on IL-34 deficiency and the Discussion address microglial abundance, CNS protection and possible roles in neurodegenerative pathology (page unavailable). Searches for transcriptomic or proteomic analyses, a homeostatic signature and aging found no passage addressing the claimed signature or its perturbation. (LLM, conf=0.77)
Experimental — accuracy not yet measuredMicroglial survival and maintenance depend on cytokines including CSF1 and IL-34 and on transcription factors such as IRF8.
“Microglial survival and maintenance depend on cytokines, including CSF1 and interleukin (IL)-3414, and on transcription factors such as IRF812.”
From Microglia in neurodegeneration (2018) · cites this paper as [14]
Microglial development depends on CSF1R and on IRF8, which is essential for development of mature A2 microglial precursors.
“the development of microglia is dependent on CSF1R, which transmits signals upon activation by its ligands CSF1 and IL-34 and serves as a survival factor68.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [68]
CSF1 acting via CSF1R is important for microglial development, and IL-34 promotes tissue-specific signalling required for differentiation of skin myeloid cells and CNS microglia.
“the cytokine CSF1, acting via its receptor CSF1R, is important for microglial development8.”
From Microglial signatures and their role in health and disease (2018) · cites this paper as [68]
Several groups have tried different culture conditions with cytokines such as CSF1, GM-CSF, TGFβ, and IL-34 to preserve homeostatic microglia signature and ramified morphology in vitro.
“Several groups have attempted different cell culture conditions to maintain homeostatic microglia signature and ramified morphology In vitro using a variety of cytokines, such as CSF1, GM-CSF, TGFβ, and IL-34 [73-76].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [74]
IL-34 and CSF1 are important for microglial differentiation and maintenance in vivo.
“IL-34 and CSF1g, important for microglia differentiation and maintenance in vivo 16,17, were added to the medium.”
From Efficient derivation of microglia-like cells from human pluripotent stem cells (2016) · cites this paper as [17]
Murine studies identified key cytokines, cell receptors, and transcription factors required for microglia development and survival in vivo.
“Recently, murine studies identified key cytokines, cell receptors, and transcription factors required for microglia development and survival in vivo.”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Wang et al., 2012
IL-34 and TGFβ-1 are among the factors required for microglia development and survival in vivo.
“These factors include IL-34 and TGFβ-1 (Butovsky et al., 2014; Greter et al., 2012; Wang et al., 2012; Yamasaki et al., 2014).”
From iPSC-derived human microglia-like cells to study neurological diseases (2017) · cites this paper as Wang et al., 2012
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- Authors
- Wang, Y., Szretter, K. J., Vermi, W., Gilfillan, S., Rossini, C., Cella, M., Barrow, A. D., Diamond, M. S., & Colonna, M.
- Affiliations
- Washington University in St. Louis (US)
- University of Brescia (IT)
- Corresponding author
- Colonna, Marco
- ORCID
- Venue
- Nature Immunology
- Published
- 2012-06-24
- Volume
- 13
- Issue
- 8
- Pages
- 753-760
- ISSN
- 1529-2908 (ISSN-L)
- 1529-2916
- PMC
- PMC3941469
- OpenAlex
- W1994581225
- Cited by
- 1,011
- References
- 59
- Citations by year
- 2026: 57 · 2025: 68 · 2024: 74 · 2023: 73 · 2022: 77 · 2021: 91 · 2020: 80 · 2019: 96 · 2018: 64 · 2017: 72 · 2016: 63 · 2015: 59 · 2014: 76 · 2013: 49 · 2012: 12
- FWCI
- 31.58
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, public-domain)
- Funders
- National Heart, Lung, and Blood Institute (HL097805, R01HL097805, T32HL007317)
- National Institute of General Medical Sciences (GM77279, R01GM077279)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020579)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- IL-34, CSF1R, Langerhans cells, microglia, keratinocytes, neurons, myeloid differentiation, dendritic cells, CSF-1, skin immunity
- MeSH terms
- Animals, Cell Differentiation, Central Nervous System, Interleukins, Langerhans Cells, Macrophages, Mice, Inbred C57BL, Neurons, Skin, West Nile Fever, West Nile virus, Keratinocytes, Macrophage Colony-Stimulating Factor, Receptor, Macrophage Colony-Stimulating Factor, Microglia, Mice, Knockout, Myeloid Cells, Myelopoiesis, Mice
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