ReviewCXCR4 signaling in health and disease
Introduction
Chemokines are small proteins (8–10 KDa), mostly basic, belonging to the cytokine superfamily. They were first described as molecules regulating leucocyte trafficking throughout the body in both physiological and pathological conditions. The first demonstration of the chemoattractant properties of chemokines consisted in a migration assay for neutrophils using interleukin-8 (IL-8) [1]. Later on, other chemokines were found to be secreted at sites of inflammation and required for proper recruitment of leukocytes to different tissues [2].
Despite their cardinal role in promoting and directing cell migration, chemokines also regulate a plethora of different homeostatic processes, such as the formation of tissues during morphogenesis, neovascularization, angiogenesis and adaptive immune responses. Remarkably, the dysregulated expression and activity of chemokines/chemokine receptors in immune cells has been implicated in various pathological conditions, including autoimmune and chronic diseases, viral infections, and cancer. Thus, understanding the mechanisms by which chemokines act in modulating immunity and inflammation represents a mandatory step for the definition of novel drugs and therapies.
To the current knowledge, there are almost 50 chemokines that bind 25 different types of receptors: while some chemokines bind a single receptor, others can interact with more than one, and, likewise, some chemokine receptors can be activated by more chemokines [3], [4].
Traditionally, the chemokine family has been classified into major subfamilies on the basis of the arrangement of the two N-terminal cysteine residues. In such motif, the C- and CC-chemokines have one or two adjacent cysteines, respectively. In the CXC-chemokine subgroup the cysteine is separated by one residue and, finally, CX3C-chemokines present three residues between the two cysteines. The CXC subfamily can be sub classified into two groups, depending on the presence of the tripeptide motif ELR (glutamic acid-leucine-arginine) at the N-terminus [5]. The CXC chemokines that display this motif exhibit angiogenic activity in vitro and in vivo [6].
According to their influence in either physiological or pathological cell traffiking, chemokines can be also divided in homeostatic versus inflammatory ones. The former, including CXCL13, CCL19, and CCL21 and CXCL12 are those constitutively expressed in a specific tissue. The latter, including CCL2, CCL3, CCL4, CCL5, CCL11, and CXCL10, are conversely up-regulated in response to inflammatory stimuli.
Chemokine receptors are commonly classified in CR, CCR, CXCR, and CX3CR receptors according to the type of chemokine they bind, and are differentially expressed on different cell types [7]. Chemokine receptors belong to the family of the 7-transmembrane receptors and, with the exception of a small group of atypical receptors (ACKR) that are not associated with G proteins and may function as scavenger for chemokines [8], activate intracellular signaling pathways by coupling to heterotrimeric G-proteins. G-proteins are coupled to the receptor through its C-terminus segment and the third intracellular loop [9].
The binding of the ligand on the appropriate chemokine receptor promotes structural changes on its cytoplasmic loops and tail, which catalyze the exchange of GDP with GTP on the α subunit of the heterotrimeric G protein [10]. The α and βγ subunits then dissociate and bind to cellular effector enzymes that generate second messengers as cAMP or IP3, which, in turn, activate distinct signaling pathways, leading to different cellular responses. Several studies have shown that, as many other GPCRs, both CC and CXC chemokine receptors undergo homo- or heterodimeration [11]. Receptor clustering in dimers or oligomers significantly increases the sensitivity and the strength of chemokine responses by organizing large functional signaling platforms at the cell surface.
Among the chemokine receptors, CXCR4 stands out for its pleiotropic roles in both physiological and pathological conditions and it represents a crucial target in drug development. In this review, we will focus on CXCR4 receptor signaling and its functional significance in health and disease.
Section snippets
The CXCR4 ligand: CXCL12
CXCL12, also known as stromal derived factor 1 (SDF-1), is a homeostatic chemokine controlling hematopoietic cell trafficking and lymphoid tissue architecture. It is ubiquitously expressed in both embryonic and adult tissues, with highest levels detected in liver, pancreas, spleen and heart [12]. In embryonic life, CXCL12 is involved in the proliferation and differentiation of immature progenitors, wherein it modulates adhesion [13] and secretion of proteolytic enzymes [14]. In adult organisms,
CXCR4 structure and expression
CXCR4 is a 7-transmembrane G-protein coupled receptor identified for the first time in peripheral blood leukocytes [27] and highly expressed in a variety of cell types, including lymphocytes, endothelial, epithelial and hematopoietic stem cells, stromal fibroblasts and cancer cells [28]. In addition to the well-established functions in hematopoiesis [29] and immune responses [30], [31], CXCR4 plays a pivotal role in a plethora of physiological processes such as neurogenesis [32], germ cell
CXCR4 signaling
As previously mentioned, CXCR4 is involved in a number of physiopathological processes. The binding of CXCL12 to CXCR4 takes place through a two-step mechanism [42]. The first CXCR4-CXCL12 contact at the extracellular domain induces a conformational change in the receptor, which strengthens chemokine binding to a receptor pocket. Next, the receptor undergoes a second conformational change that activates the intracellular trimeric G protein by the dissociation of Gα subunit from the Gβ/Gγ dimer
CXCR4 in the bone marrow niche
All blood cells, including lymphocytes and myeloid cells, are generated in the bone marrow (BM) from a multipotent cell lineage named hematopoietic stem cells (HSCs). CXCR4-CXCL12 axis is fundamental for BM colonization during ontogenesis, as well as for HSCs homeostasis [66]. Inside the bone marrow, the HSC niche is maintained by a number of cell types producing high titers of CXCL12, including stromal cells and CXCL12-abundant reticular (CAR) cells [67], osteoblasts [68], nestin-expressing
CXCR4 in immune responses
Besides regulating BM homeostasis, CXCR4 plays a prominent function in orchestrating both innate and adaptive immune responses: it regulates leucocyte trafficking and distribution from and to peripheral tissues, participates in lymph node organization [77], and finally it sustains T cell priming by contributing to formation and stabilization of the IS [58], [65].
During bacterial infection, CXCR4, along with the integrin CD11b, mediates neutrophil re-localization via lymphatic vessels from
CXCR4 in diseases: the WHIM Syndrome
The prominent role of CXCR4 in several diseases including cancer, autoimmunity, and immunodeficiencies has been largely documented.
In cancer, the CXCL12/CXCR4 axis sustains tumor cell survival, proliferation and migration [89]. Indeed, CXCR4 expression has been identified as a prognostic marker for several kinds of human cancers [90], including breast, ovarian, and pancreatic adenocarcinoma. One of the key events in cancer spreading is the targeting of secondary site of tumor growth and CXCR4
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Acknowledgements
The authors wish to thank Telethon Foundation, the European Union’s Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 602363 and the ERC Advance Grant under grant agreement no. 322823 to AV.
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