CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

Abstract

Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or β-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca 2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.

Immunosenescence in Choroidal Neovascularization (CNV)—Transcriptional Profiling of Naïve and CNV-Associated Retinal Myeloid Cells during Aging

“…On the other hand, our study identified 422 age-dependent genes, such as Cxcl14, Vcam1, and Spp1, that are differentially expressed in senescent retinal MCs and contribute to biological functions such as chemotaxis, cell adhesion, and cell proliferation. In particular, CXCL14 (which synergistically acts together with CXCL13) could contribute to the recruitment of further immune cells in the aged retina [32]. In addition, we found the upregulation of various age-dependent factors, such as Itgax, Lgals3, Axl, Cst7, Clec7a, and Spp1 (see Figure 2A-C for Lgals3 and Spp1) in aged myeloid cells, which was in accordance with studies exploring the expression profile of senescent brain microglia [33][34][35][36][37].…”

Reduced Incidence of Necrotizing Enterocolitis due to the Anti-Inflammatory Effects of CXCL14 in Intestinal Tissue

“…CXCL14 (or BRAK or MIP-2 γ ), a member of the CXC family, is encoded by the chemokine (C-X-C Motif) ligand 14 genes located on human chromosome 5q31; previous researches demonstrate that the main functions of CXCL14 are immune regulation [ 19 , 20 ], anti-inflammatory [ 21 ], fibrosis [ 22 ], angiogenesis [ 23 ] and cancer progression [ 24 ]. More and more attention has been paid to research concerning the CXCL14 in acute immune including the chemotaxis and differentiation of immune cells [ 25 ], immunological surveillance [ 26 ].…”

Spatial determinates of effector and memory CD8+ T cell fates*

“…This efficiently reduces chemokine concentration in a precise region and generates a negative gradient, thus promoting directional cell migration away from that region. In addition, allosteric chemokines such as CXCL14, act in concert with existing chemokine gradients to promote chemotaxis, while having no individual effect 117 . Combined, lymphocytes need to incorporate multiple chemokine signals from different directions and make a collective decision on migratory direction.…”

“…In addition, allosteric chemokines such as CXCL14, act in concert with existing chemokine gradients to promote chemotaxis, while having no individual effect. 117 Combined, lymphocytes need to incorporate multiple chemokine signals from different directions and make a collective decision on migratory direction. It is not well understood, how T cells make these decisions (Figure 1).…”