Abstract
Intestinal macrophages (mφ) form one of the largest populations of mφ in the body and are vital for the maintenance of gut homeostasis. They have several unique properties and are derived from local differentiation of classical Ly6Chi monocytes, but the factors driving this tissue-specific process are not understood. Here we have used global transcriptomic analysis to identify a unique homeostatic signature of mature colonic mφ that is acquired as they differentiate in the mucosa. By comparing the analogous monocyte differentiation process found in the dermis, we identify TGFβ as an indispensable part of monocyte differentiation in the intestine and show that it enables mφ to adapt precisely to the requirements of their environment. Importantly, TGFβR signaling on mφ has a crucial role in regulating the accumulation of monocytes in the mucosa, via mechanisms that are distinct from those used by IL10.
Highlights
Macrophages are present in most tissues of the body, where they scavenge dying cells, remodel tissues and act as sources of growth factors for neighboring parenchymal cells and leukocytes.[1]
The discovery that the yolk sac mesenchyme, fetal monocytes, and adult bone marrow (BM) derived monocytes could all generate resident mf led to the idea that tissue-specific differences among mature mf might reflect their origin from distinct precursors
Newly arrived monocytes are Ly6ChiMHCII– CX3CR1int (P1), two intermediate subsets can be identified as Ly6ChiMHCII þ CX3CR1int (P2) and Ly6C–MHCII þ CX3CR1int (P3); mature mf are Ly6C–MHCII þ CX3CR1hi (P4)[8,18] (Figure 1b)
Summary
Macrophages (mf) are present in most tissues of the body, where they scavenge dying cells, remodel tissues and act as sources of growth factors for neighboring parenchymal cells and leukocytes.[1]. The discovery that the yolk sac mesenchyme, fetal monocytes, and adult bone marrow (BM) derived monocytes could all generate resident mf led to the idea that tissue-specific differences among mature mf might reflect their origin from distinct precursors. Microglia are derived almost entirely from self-renewal of yolk sac precursors,[4,5,6] alveolar mf, liver Kupffer cells, and epidermal Langerhans cells are derived from fetal liver monocytes.[5,6,7] we have shown that intestinal mf require constant replenishment by BM-derived monocytes throughout adult life.[8,9] Adult monocyte-derived mf are present to different degrees in other tissues such as dermis,[10] heart,[11,12,13] and the serous cavities.[14] more recent work makes it clear that developmental origin alone does not explain the heterogeneity seen among mf from different anatomical sites, as these have unique molecular signatures even when derived from the same progenitor.[15] transcriptionally identical mf develop upon adoptive transfer into the neonatal lung, irrespective of the type of precursor used.[16] tissuederived signals appear to be the principal determinant of resident mf fate
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