Nonredundant roles of keratinocyte‐derived IL‐34 and neutrophil‐derived CSF1 in Langerhans cell renewal in the steady state and during inflammation

Abstract

IL-34 and colony stimulating factor 1 (CSF1) are two alternative ligands for the CSF1 receptor that play non-redundant roles in the development, survival and function of tissue macrophages and Langerhans cells (LCs). In this study, we investigated the spatio-temporal production of IL-34 and its impact on skin LCs in the developing embryo and adult mice in the steady state and during inflammation using Il34LacZ reporter mice and newly generated inducible Il34-knockout mice. We found that IL-34 is produced in the developing skin epidermis of the embryo, where it promotes the final differentiation of LC precursors. In adult life, LCs required IL-34 to continually self-renew in the steady-state. However, during UV-induced skin damage, LCs regeneration depended on neutrophils infiltrating the skin, which produced large amounts of CSF1. We conclude that LCs require IL-34 when residing in fully differentiated and anatomically intact skin epidermis, but rely on neutrophil-derived CSF1 during inflammation. Our demonstration that neutrophils are an important source of CSF1 during skin inflammation may exemplify the mechanism through which neutrophils promote their subsequent replacement with mononuclear phagocytes.

Regulation of Embryonic and Postnatal Development by the CSF-1 Receptor

“…In the developing mouse embryo, CSF-1, but not IL-34, is expressed in the YS (Johnson & Burgess, 1978; Wang et al, 2016). While CSF-1R signaling is crucial for the development of E12.5 YS primitive MΦ, absence of IL-34 does not affect their production or liver monocytopoiesis at E18.5 (Wang et al, 2016). These data suggest that CSF-1 is the primary regulator of embryonic MΦ development.…”

“…IL-34 primarily regulates the development and maintenance of Langerhans cells, whereas regulation of microglia is shared with CSF-1, in a brain region-specific manner (Chitu et al, 2016; Ginhoux et al, 2010; Greter et al, 2012; Wang et al, 2012). An interesting example of nonredundant sequential regulation by CSF-1 and IL-34 has been documented in LC development (Dai et al, 2002; Wang et al, 2016). CSF-1R is essential for the development and maintenance of LC (Ginhoux et al, 2006).…”

“…CSF-1R is essential for the development and maintenance of LC (Ginhoux et al, 2006). LC are reduced in newborn, but recover in adult Csf1 op/op mice (Cecchini et al, 1994; Dai et al, 2002), while Il34 − / − mice have a severe reduction in LC throughout life (Greter et al, 2012; Wang et al, 2012, 2016), suggesting that both CSF-1 and IL-34 contribute to LC development but that IL-34 alone is required for LC maintenance. Wang et al (2016) showed that in the developing skin IL-34 expression commences at E17.5, is high in the epidermis and low in the dermis, while CSF-1 exhibits the opposite pattern.…”

“…LC are reduced in newborn, but recover in adult Csf1 op/op mice (Cecchini et al, 1994; Dai et al, 2002), while Il34 − / − mice have a severe reduction in LC throughout life (Greter et al, 2012; Wang et al, 2012, 2016), suggesting that both CSF-1 and IL-34 contribute to LC development but that IL-34 alone is required for LC maintenance. Wang et al (2016) showed that in the developing skin IL-34 expression commences at E17.5, is high in the epidermis and low in the dermis, while CSF-1 exhibits the opposite pattern. IL-34 is not necessary for the infiltration and survival of LC precursors in the immature dermis (possibly because of high local levels of CSF-1) but is necessary to promote the proliferation and survival of LC precursors in the mature epidermis.…”

“…However, the significance of this heterotetramer in vivo is unclear, as the expression patterns of IL-34 and CSF-1 are mostly nonoverlapping. For example, IL-34 is highly expressed in epidermis and forebrain and low in the female reproductive tract, dermis, heart, and hindbrain, where CSF-1 is highly expressed (Chitu et al, 2016; Nandi et al, 2012; Wang et al, 2016; Wei et al, 2010). …”