Monocyte Selectivity and Tissue Localization Suggests a Role for Breast and Kidney–Expressed Chemokine (Brak) in Macrophage Development

Abstract

Although numerous chemokines act on monocytes, none of them is specific for these cells. Here, we show that breast and kidney–expressed chemokine (BRAK) is a highly selective monocyte chemoattractant. Migration efficacy and Bordetella pertussis toxin–sensitive Ca2+ mobilization responses to BRAK were strongly enhanced after treatment of monocytes with the cyclic AMP–elevating agents prostaglandin E2 and forskolin. BRAK is the first monocyte-selective chemokine, as other types of blood leukocytes or monocyte-derived dendritic cells and macrophages did not respond. Expression in normal skin keratinocytes and dermal fibroblasts as well as lamina propria cells in normal intestinal tissues suggests a homeostatic rather than an inflammatory function for this chemokine. In addition, macrophages were frequently found to colocalize with BRAK-producing fibroblasts. We propose that BRAK is involved in the generation of tissue macrophages by recruiting extravasated precursors to fibroblasts, which are known to secrete essential cytokines for macrophage development.

Prostaglandin E2 modulates the functional responsiveness of human monocytes to chemokines

“…In addition, a study by Kurth et al [23] Of note, our data show that PGE 2 exerts its effects on human monocytes independently of chemokine receptor expression. Thus, PGE 2 may act by completing the engagement of signaling modules downstream of the chemokine receptors to facilitate signaling and migratory function.…”

Murine CXCL14 Is Dispensable for Dendritic Cell Function and Localization within Peripheral Tissues

“…As human CXCL14 was shown to be involved in monocyte and DC recruitment (19,42,44,46), these subsets were analyzed in more detail in blood, spleen, bone marrow, and peripheral lymph nodes ( Fig. 2A and B).…”

“…To address the question whether murine CXCL14 could be involved in the homeostatic recruitment of monocytes and/or DC precursors toward the periphery, various tissues were examined for the presence of macrophages and DCs. Due to the prominent expression of CXCL14 in the human epidermis (19,42), emphasis was placed on normal (uninflamed) murine skin. Epidermal sheets from CXCL14 Ϫ/Ϫ mice stained with an anti-major histocompatibility complex class II (MHC-II) antibody showed normal numbers of LCs.…”

“…Strong expression of CXCL14 in healthy human skin (19,42), which is not further upregulated in skin diseases, such as atopic dermatitis (19) and psoriasis (data not shown), indicates a homeostatic as opposed to inflammatory role for this chemokine (25,26). We have shown previously that human CXCL14 attracts blood monocytes and CD14 ϩ DC precursors generated during in vitro culture of CD34 ϩ hematopoietic progenitor cells (19,42). We were unable to detect alternative CXCL14-responsive cell types, such as LCs and DCs, or other cell lineages like T, B, and NK cells.…”

“…CXCL14 is also present in various tumors of epithelial origin, but the level of expression is heterogeneous, with the majority showing a downregulation with respect to healthy tissue (4,9,15,19,43,44,46). Recently, we have shown that human CXCL14 is selective for blood monocytes and CD14 ϩ DC precursors, either derived from CD34 ϩ hematopoietic progenitor cells or isolated from blood (19,42). The prominent expression in normal epidermis as well as on blood vessels in the superficial dermal plexus led us to propose the hypothesis that human CXCL14 might contribute to the recruitment of cutaneous DCs under steady-state conditions.…”