Cytokine 109 (2018) 76–80 Contents lists available at ScienceDirect Cytokine journal homepage: www.elsevier.com/locate/cytokine Regulation of hematopoiesis by the chemokine system a Ornella Bonavita , Valeria Mollica Poeta ⁎ Raffaella Bonecchia,b, a b c a,b a , Matteo Massara , Alberto Mantovani T a,b,c , Humanitas Clinical and Research Center, via Manzoni 56, 20089 Rozzano (MI), Italy Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini, 20090 Pieve Emanuele (MI), Italy The William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK A R T I C L E I N F O A B S T R A C T Keywords: Chemokines Chemokine receptors Hematopoiesis Myelopoiesis Although chemokines are best known for their role in directing cell migration, accumulating evidence indicate their involvement in many other processes. This review focus on the role of chemokines in hematopoiesis with an emphasis on myelopoiesis. Indeed, many chemokine family members are an important component of the cytokine network present in the bone marrow that controls proliferation, retention, and mobilization of hematopoietic progenitors. 1. The chemokine system Chemokines are a large family of chemotactic cytokines consisting of more than 50 molecules. The name “chemo-kines” derives from their capacity to cause chemotaxis in responsive cells, which express related chemokine receptors. Chemokines have low amino acid sequence homology, but they all have a conserved tertiary structure, consisting of a disordered amino-terminus, three-stranded antiparallel β-sheet and a carboxy-terminal α-helix [2]. Depending on the position of the cysteine residues in their N-terminus, chemokines are divided in four subfamilies: CC, CXC, C and CX3C [54,19]. The chemokine subfamilies CC, CXC and CX3C have four well-conserved cysteine residues, which form two disulphide bonds between the first and the third cysteine and between the second and the fourth cysteine. The CC chemokines are the largest subfamily of chemokines and have the first two of the four cysteine residues in adjacent position, while the CXC and CX3C chemokines have one and three amino acids separating the two cysteines, respectively. The CXC chemokines can be further subdivided in ERL− and ERL+ chemokines, based on the presence or absence of the ELR (Glu-Leu-Arg) motif [40]. In general, ERL− chemokines exhibit an anti-angiogenic activity, whereas ERL+ chemokines are angiogenic factors [60,61]. Finally, the XC subfamily is composed by only two chemokines having only two cysteines in their sequence. Based on their expression pattern, chemokines can be also classified as homeostatic or inflammatory ones [34]. Homeostatic chemokines (e.g. CXCL12, CXCL13, CCL14, CCL19) are constitutively produced and regulate basal leukocyte trafficking, such us lymphocyte homing to secondary lymphoid organs. Inflammatory chemokines (e.g. CCL2, CCL5, CXCL8) are inducible molecules secreted during inflammatory responses, upon infection or tissue injury and they drive leukocyte recruitment to the site of inflammation. The specific function of each chemokine is determined by the expression of chemokine receptors on target cells [5].Chemokine receptors are 7-transmembrane (7TM) receptors coupled to hetero-trimeric GTP-binding proteins (G-protein) of the Gi type, sensitive to Bordetella pertussis toxin. Depending on the chemokines they bind, chemokine receptors are classified as CXCR, CCR, CX3CR, or XCR and can be either inflammatory or homeostatic [47]. Beyond canonical chemokine receptors, a smaller family of atypical chemokine receptors (ACKRs) has been identified [4]. ACKRs share many similarities with canonical chemokine receptors and bind ligands with high affinity but show structural modifications in the motif that is essential for G-protein interaction. As result, ACKRs are unable to couple to G protein and to promote cell migration [8], and they act as scavengers, transporters or depots for the chemokines they bind. The family of ACKRs includes four receptors named ACKR1 (previously called DARC), ACKR2 (D6), ACKR3 (CXCR7), and ACKR4 (CCX-CKR) [4]. Most studies on chemokines and chemokine receptors were focused on their ability to chemoattract leukocytes. However, it is known from several years that chemokines regulate additional functions in leukocytes. For instance, CXCR2 ligands regulate effector functions of neutrophils [6] and CCL19, acting on CCR7 expressed by dendritic cells, Abbreviations: HSCs, hematopoietic stem cells; CMPs, common myeloid progenitors; GMPs, granulocytes-macrophages progenitors; ACKRs, atypical chemokine receptors; MEPs, megakaryocyte-erythrocyte progenitors; HPCs, hematopoietic progenitor cells; NECs, nucleated erytrocyte precursors ⁎ Corresponding author at: Humanitas Clinical and Research Center, Humanitas University, Via Manzoni 56, 20089 Rozzano, Italy. E-mail address: raff[email protected] (R. Bonecchi). https://doi.org/10.1016/j.cyto.2018.01.021 Received 16 October 2017; Received in revised form 19 January 2018; Accepted 24 January 2018 1043-4666/ © 2018 Elsevier Ltd. All rights reserved. Cytokine 109 (2018) 76–80 O. Bonavita et al. including chemokines. regulates their survival [55]. Here, we resume data on the role of chemokines in the control of differentiation, mobilization, and proliferation of hematopoietic progenitors. 4. Chemokines in hematopoiesis 2. Hematopoiesis The role of chemokines and their receptors in hematopoiesis encompasses the regulation of proliferation as well as the survival and the retention of hematopoietic progenitors. In particular the CXCL12CXCR4 axis is fundamental for HSC homeostasis [30] and at least 24 chemokines belonging to CC, CXC and C families have been reported to be endowed with myelosuppressive activity in vivo e in vitro [17,28,37,14,67,10,11]. In this review, we seek to resume data on the main chemokines and chemokine receptors that have been found involved in the regulation of homeostatic hematopoiesis. Hematopoiesis is a dynamic process by which hematopoietic stem cells (HSCs) proliferate and differentiate into mature blood cellular components. HSCs are a rare population of cells characterized by an extensive self-renewal capability and pluripotency. The division of HSCs can result in the production of additional HSCs or hematopoietic progenitor cells (HPCs), that have a limited self-renewal capability and consist of cells in which multipotency is restricted [33,1,32]. In adult life, hematopoiesis takes place into the bone marrow (BM) whereas during fetal development, since BM is not yet developed, liver, thymus and spleen may assume hematopoietic function [7]. Histological analysis revealed that during adulthood, HSCs are mainly located in restricted areas of BM, called as BM HSC niches consisting of both hematopoietic and non-hematopoietic cell types. In particular, HSCs are associated with cells of mesenchymal origin, sinusoidal endothelium, and with arterioles [20]. HSC niche represents a complex microenvironment that provides the signals necessary to maintain physiological homeostasis and to achieve the balance between HSC renewal and differentiation. These signals can enhance or suppress the growth, survival and movement of HSCs and progenitor cells. Adhesion molecules such us P-selectin, E-selectin and vascular cell adhesion molecules (VCAM-1) are expressed by niche stromal cells and control HSC maintenance and function by the interaction with their specific receptors on HSCs [41]. On the other hand, the niche elaborates also many cytokines and growth factors, such as stem cell factor (SCF), interleukin-3 (IL-3), interleukin-6 (IL-6) and colony-stimulating factors (CSFs), that are essential for the initial rounds of cell division and differentiation of HSCs [46]. As we will discuss below, an important player in the interaction between HSCs and the niche is the CXCR4/CXCL12 axis [63]. 4.1. CXCL12-CXCR4 axis The chemokine CXCL12, also known as stromal derived factor-1 (SDF-1), is a representative homeostatic chemokine and it is expressed constitutively in the BM. CXCL12 is produced by a wide variety of cells in the niche, including perivascular mesenchymal stromal cells (MSCs), endothelial cells, osteoblasts, some hematopoietic cells, and by adipogenic progenitor cells with reticular shape [65,44]. The last cell type, given its profuse production of CXCL12, is named CXCL12-abundant reticular (CAR) cells and they are in close contact with HSCs. The production of CXCL12 by these cells is fundamental for the homeostasis of the hematopoietic niche [9]. Indeed, the binding of CXCL12 to the receptor CXCR4, expressed on HSCs, induces their retention in the BM. The relevance of the CXL12-CXCR4 axis is demonstrated by the fact that the CXCR4 antagonist AMD3100 (Plerixafor) is an approved drug for the mobilization of HSCs [22]. Moreover, the retention signal induced by the CXCL12-CXCR4 axis is also the target of proteolytic enzymes, such as Elastase, Cathepsin-G and CD26 that are known to induce HSC mobilization. Indeed, it has been demonstrated that these enzymes exert their mobilization activity by cleaving the N-terminal sequence of CXCL12. These NH2-cleaved versions of CXCL12 are characterized by decreased activity or even an antagonistic effect to the uncleaved chemokine [46]. Interestingly, it was found that also G-CSF exerts its HSC mobilization effect through neutrophil activation and release of proteases, including MMP-9, that results in enhanced cleavage of c-kit, CXCL12, CXCR4, VCAM-1 and its receptor Very Late Antigen-4 (VLA-4) [62]. However, CXCL12 provides a retention signal for many other cells expressing CXCR4 in the BM, including committed progenitors and neutrophils [25]. In addition to control HSC retention in the BM, CXCL12 by interacting with CXCR4, has other important effects on hematopoiesis and myelopoiesis. This crucial role is corroborated by significant phenotypic changes in the hematopoietic system of mice lacking Cxcl12 or Cxcr4 genes. These mice, that have a late gestation lethal phenotype due to defective cardiac septum formation, have also defects in B-cell lymphopoiesis and virtually absent BM myelopoiesis [39,31]. In addition, the deletion of one copy of CXCR4 is sufficient to give a selective advantage for BM engraftment of HSCs. Indeed, Cxcr4 haploinsufficiency enhanced HSC proliferation while maintaining long-term hematopoiesis [43]. Furthermore, CXCL12 regulates HSC mitochondrial respiration that is essential to maintain their undifferentiated state [45]. These observations indicate that CXCL12, beside its role in BM retention, has a role in keeping HSC quiescence, and maintaining a constant pool of HSCs to sustain hematopoiesis. Behind its direct effect on HSCs, CXCL12 can also indirectly have impact on hematopoiesis. Studies in CXCR4-deficient mice have shown that the CXCL12–CXCR4 axis, by regulating the development of vasculature, can have a crucial effect on the stucture of the hematopoietic niche near the sinusoids [64]. 3. Myelopoiesis Myelopoiesis specifically refers to the process that leads to myeloid cell production [7]. Myeloid cells derive from HSC differentiation into common myeloid progenitors (CMPs) that are cells committed to the myeloid lineage, and give rise to granulocyte-macrophage progenitors (GMPs) and megakaryocyte-erythrocyte progenitors (MEPs). Next, the differentiation of GMPs and MEPs gives rise to whole lineage of myeloid cells, including monocytes, macrophages, granulocytes, platelets, erythrocytes, and dendritic cells (DCs) [33,1,32]. It has been demonstrated in mice that tissue resident macrophages in liver (Kupffer cells), spleen (red pulp macrophages), brain (microglia), epidermis (Langerhans cells), lung (alveolar macrophages), peritoneum (large peritoneal macrophages), pancreas, kidney and heart (F4/80bright macrophages) originate from precursor cells in the yolk sac. They are long-lived and can proliferate within their tissue of residence [35,66]. However, with the exception of microglia, tissue resident macrophages are progressively replaced by BM-derived progenitors throughout the lifespan of the animal [52]. The cytokines of the colony stimulating factor (CSF) family are the major orchestrators of myelopoiesis; they were defined by their abilities to generate in vitro colonies of mature myeloid cells from BM precursor cells, and they include: macrophage CSF (M-CSF; also known as CSF1), which supports macrophage differentiation; granulocyte-macrophage colony stimulating factor (GM-CSF; also known as CSF2), that stimulate the proliferation and differentiation into monocytes and DCs; and granulocyte colony stimulating factor (G-CSF; also known as CSF3), which is important for the differentiation of neutrophil progenitors and precursors [46]. However, within the microenvironment where HPCs reside, they are likely influenced by a huge number of other cytokines, 77 Cytokine 109 (2018) 76–80 O. Bonavita et al. 4.2. CCL3 and CCR1 4.4. CCL5 In the context of hematopoiesis, CCL3/MIP-α is one of the best studied chemokine. CCL3 was first identified as a suppressor molecule for spleen colony formation units (CFU-s), and then for multi-growth factor responding cells (CMP) [17,28]. Moreover, CCL3 can maintain a quiescent state in HSCs by blocking cell cycle entry [17,13]. Interestingly, it has been demonstrated that basophils in the BM are an important source of CCL3 and that upon BM transplantation, the genetic deletion of Cccl3 gene in donor cells or the deletion of basophils, caused exaggerated reconstitution of donor-derived hematopoietic cells. Because of its suppressive activity, CCL3 was suggested to act as a myeloprotective agent by placing HSCs and progenitors in a slowly cycle state, that could be less sensitive to chemotherapy [3]. In addition using Ccl3−/− mice it was recently demonstrated that this chemokine is essential for the regulation of the proliferation of HSCs [59]. The receptor mediating CCL3 myelosuppressive effect is still unidentified. Indeed, CCL3 is able to bind four chemokine receptors, CCR1, CCR3, CCR5 and ACKR2 but none of the specific knock out mice reverted the CCL3 inhibitory function [50]. Thus, it is possible to speculate that the CCL3 myelosuppressive function is mediated by a still unidentified receptor or by the combination of more than one known receptors. Even though CCR1 is not a dominant receptor for suppression of CMPs and GMPs, it has been demonstrated to mediate the myelopoietic effect of CCL3 on more mature myeloid progenitors [13]. Indeed, CCL3 enhances the proliferation of mature and committed myeloid progenitors that respond to a single growth factor (CFU-G and CFU-M). However, the in vivo relevance of this effect is not understood because no significant differences in CMPs and GMPs proliferation were observed in CCR1 deficient versus WT mice [16,13]. CCL3, in addition to control the proliferation of myeloid progenitors, regulates the mobilization of primitive progenitors with marrow repopulating activity, by interacting mainly with CCR1 but not CCR5 [38]. The chemokine CCL5, appears to play a role in promoting myelopoiesis. Indeed, mice lacking CCL5 exhibited unbalanced hematopoiesis, having decreased myeloid progenitors and an increase in T cells and lymphoid-biased HSCs. In contrast, overproduction of CCL5 by retroviral expression in BM progenitors caused a deficit of T-cell output concomitant with an increase in myeloid progenitors [26,68]. Since high levels of the inflammatory chemokine CCL5 are found in the aging hematopoietic niche, these observations suggest that aging-related myeloid skewing phenotype, which may contribute to age-associated immune deficiency, can result from increased expression of this chemokine. Since CCL5 binds four receptors, CCR1, CCR3, CCR5, and ACKR2, at now it is not known which one is mediating the induction of myeloid differentiation pathway. 4.5. CXCR2 and its ligands Among CXC chemokines the CXCR2 ligands CXCL8, CXCL2 and the murine homologs CXCL1 and CXCL2, were reported to inhibit the proliferation of immature myeloid progenitors in vitro [12]. The myelosuppressive activity of these CXC chemokines has been assessed in vivo by the use of gene targeted mice deleted for their receptor CXCR2. In these mice, there is an expansion of CMPs, GMPs, and MEPs and CXCL8 and CXCL2 do not inhibit their proliferation [12]. Moreover, in mice lacking CXCR2 it was observed an increased number of mature neutrophils, indicating that this receptor is also a regulator of neutrophil differentiation [18]. In addition, the myelosuppressive function of CXCL8 was demonstrated also in the human system [15]. These results have been recently confirmed and extended by transcriptomic analysis of human HSCs indicating that several CXC chemokines (CXCL1-4, 6, 10, 11, and 13) are upregulated in human quiescent HSCs compared to the proliferating one and that CXCR2 is required for the HSC survival and self-renewal [58]. Thus, CXCR2 has been identified as a negative regulator of HSCs, CMPs, GMPs, and MEPs proliferation by mediating the suppressive activity of CXCL8 and CXCL2. Several CXCR2 ligands, including CXCL1, CXCL2, and CXCL8 control also the mobilization of HPCs into peripheral blood in mice and monkeys. However, it is not known if it is a direct effect on HSCs or an indirect effect mediated by the neutrophil proteases on CXCL12 and CXCR4 [51]. 4.3. CCR2 and its ligands CCR2 is a dominant receptor for the suppression of myelopoiesis. Indeed, mice lacking CCR2 showed increased cycling status of CMPs in BM. Surprisingly, CCR2 deficiency did not affect the absolute number of HPCs in BM and spleen compared to WT. This effect was due to the control exerted by CCR2 on the proliferation and apoptosis of HPCs. Indeed, Ccr2−/− HPCs showed a balance between enhanced proliferation and apoptosis [53]. The effect of CCR2 may be mediated by CCL2, CCL13 as well as CCL12, since these CCR2 ligands, not CCL8 or CCL7, are myelosuppressive [67]. CCR2, in addition to control the proliferation of CMPs, has a crucial role in the mobilization of HSCs and mature myeloid cells, such as monocytes and neutrophils, from BM to the peripheral blood. It has been shown that during hematopoiesis, as HSCs differentiate along the myeloid lineage, CCR2 expression increases and mediates also the trafficking of HSCs, CMPs, and GMPs to the site of inflammation [57]. Interestingly, in various myeloid cell lines, CCR2 gene has been identified as one of the several targets of G-CSF during neutrophilic differentiation. Recently, CCR2 expression, which was previously supposed to be restricted to monocytes, has been described in a subset of murine BM neutrophils [29]. This expression has been demonstrated to influence neutrophil egress from the BM. Indeed, analysis performed in Ccr2-RFP+/− mice (with intact CCR2 expression) and Ccr2-RFP+/+ mice (CCR2 deficient) had shown that Ccr2-RFP+/+ mice have a small but statistically significant decrease in the number of neutrophils in the blood, LNs and spleen [27]. 4.6. CXCL4 CXCL4, previously called platelet factor-4 (PF-4), is a CXC chemokine produced by megakaryocytes and stored in platelet α-granules. The release of CXCL4 by megakaryocytes, located near the sinusoids in the BM, promotes HSC quiescence [49]. It was reported that CXCL4 induces quiescence by increasing the interaction between HPCs and the chondroitin sulfate-containing moiety [24]. However, it is not known whether CXCL4 can exert its suppressive function through interaction with the chemokine CXCL8 or with the receptor CXCR3B [49]. 4.7. The role of ACKRs The study of ACKRs in hematopoiesis is just at its infancy but emerging data indicate that they are important regulators of this process. In a recent paper, Duchene et al. found that ACKR1, expressed by BM nucleated erythroid cells (NECs), promotes their direct interaction with HSCs. They demonstrated that this interaction is required for physiological hematopoiesis because the lack of erythroid ACKR1 resulted in decreased number of HPCs, altered differentiation, and neutrophil dysfunction [23,36]. These data give also explanation of the neutropenia that characterizes healthy individuals of African ancestry and is linked with one variant of the gene encoding ACKR1. However, it is still unknown how ACKR1 is affecting HSCs, through the binding of 78 Cytokine 109 (2018) 76–80 O. Bonavita et al. Fig. 1. Chemokine and chemokine receptors involved in myelopoiesis. CXCL12 and CXCL4, acting on CXCR4 and an unknown receptor on HSCs, promote their BM retention and quiescence. CXCL2 and CXCL8, acting on CXCR2, and CCL3, acting on an unknown receptor on HSCs, induce quiescence. CCR1 and CCR2 inhibit CMP and GMP proliferation and induce their BM mobilization. On the contrary, CCL5, acting on an unknown receptor, promotes CMP and GMP proliferation. ACKR1 expressed by NECs regulates the differentiation of neutrophils; ACKR2 expressed by HSCs regulates mobilization and differentiation of myeloid cells. Chemokine receptor ligands are indicated in brackets. chemokines or other chemokine receptors. Another ACKR regulating hematopoiesis is ACKR2. Ackr2−/− mice have increased number of circulating inflammatory monocytes [56], and in humans a polymorphism of ACKR2 was reported to be linked to altered number of circulating monocytes [21]. We have recently found that Ackr2 deficiency in the hematopoietic compartment led to increased myeloid differentiation of HPCs [42] indicating that ACKR2 may also regulate pathways involved in HPC differentiation. Finally, ACKR3 is a high affinity receptor for CXCL12, a chemokine highly involved in the homing and survival of HSCs in the BM (see above). There are evidences indicating that ACKR3 modulates CXCR4 responses [48], but it is still unknown whether the CXCL12/ACKR3 axis could regulate HSC biology. [2] S.J. Allen, S.E. Crown, T.M. Handel, Chemokine: receptor structure, interactions, and antagonism, Annu. Rev. Immunol. 25 (2007) 787–820. [3] T. Baba, Y. Tanabe, S. Yoshikawa, Y. Yamanishi, S. Morishita, N. Komatsu, H. Karasuyama, A. Hirao, N. Mukaida, MIP-1alpha/CCL3-expressing basophillineage cells drive the leukemic hematopoiesis of chronic myeloid leukemia in mice, Blood 127 (2016) 2607–2617. [4] F. Bachelerie, A. Ben-Baruch, A.M. Burkhardt, C. Combadiere, J.M. Farber, G.J. Graham, R. Horuk, A.H. Sparre-Ulrich, M. Locati, A.D. Luster, A. Mantovani, K. Matsushima, P.M. Murphy, R. Nibbs, H. Nomiyama, C.A. Power, A.E. Proudfoot, M.M. Rosenkilde, A. Rot, S. Sozzani, M. Thelen, O. Yoshie, A. Zlotnik, International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors, Pharmacol. Rev. 66 (2014) 1–79. [5] M. Baggiolini, Chemokines and leukocyte traffic, Nature 392 (1998) 565–568. [6] M. Baggiolini, A. Walz, S.L. Kunkel, Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils, J. Clin. Invest. 84 (1989) 1045–1049. [7] A. Birbrair, P.S. Frenette, Niche heterogeneity in the bone marrow, Ann. N.Y. Acad. Sci. 1370 (2016) 82–96. [8] R. Bonecchi, G.J. Graham, Atypical chemokine receptors and their roles in the resolution of the inflammatory response, Front. Immunol. 7 (2016) 224. [9] P.E. Boulais, P.S. Frenette, Making sense of hematopoietic stem cell niches, Blood 125 (2015) 2621–2629. [10] H.E. Broxmeyer, Regulation of hematopoiesis by chemokine family members, Int. J. Hematol. 74 (2001) 9–17. [11] H.E. Broxmeyer, Chemokines and chemokine receptors in hematopoiesis and immunology, Exp. Hematol. 34 (2006) 965–966. [12] H.E. Broxmeyer, S. Cooper, G. Cacalano, N.L. Hague, E. Bailish, M.W. Moore, Involvement of Interleukin (IL) 8 receptor in negative regulation of myeloid progenitor cells in vivo: evidence from mice lacking the murine IL-8 receptor homologue, J. Exp. Med. 184 (1996) 1825–1832. [13] H.E. Broxmeyer, S. Cooper, G. Hangoc, J.L. Gao, P.M. Murphy, Dominant myelopoietic effector functions mediated by chemokine receptor CCR1, J. Exp. Med. 189 (1999) 1987–1992. [14] H.E. Broxmeyer, C.H. Kim, Regulation of hematopoiesis in a sea of chemokine family members with a plethora of redundant activities, Exp. Hematol. 27 (1999) 1113–1123. [15] H.E. Broxmeyer, B. Sherry, S. Cooper, L. Lu, R. Maze, M.P. Beckmann, A. Cerami, P. Ralph, Comparative analysis of the human macrophage inflammatory protein family of cytokines (chemokines) on proliferation of human myeloid progenitor cells. Interacting effects involving suppression, synergistic suppression, and blocking of suppression, J. Immunol. 150 (1993) 3448–3458. [16] H.E. Broxmeyer, B. Sherry, L. Lu, S. Cooper, C. Carow, S.D. Wolpe, A. Cerami, Myelopoietic enhancing effects of murine macrophage inflammatory proteins 1 and 2 on colony formation in vitro by murine and human bone marrow granulocyte/ macrophage progenitor cells, J. Exp. Med. 170 (1989) 1583–1594. [17] H.E. Broxmeyer, B. Sherry, L. Lu, S. Cooper, K.O. Oh, P. Tekamp-Olson, B.S. Kwon, A. Cerami, Enhancing and suppressing effects of recombinant murine macrophage inflammatory proteins on colony formation in vitro by bone marrow myeloid progenitor cells, Blood 76 (1990) 1110–1116. [18] G. Cacalano, J. Lee, K. Kikly, A.M. Ryan, S. Pitts-Meek, B. Hultgren, W.I. Wood, M.W. Moore, Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog, Science 265 (1994) 682–684. [19] I.F. Charo, R.M. Ransohoff, The many roles of chemokines and chemokine receptors in inflammation, N. Engl. J. Med. 354 (2006) 610–621. 5. Concluding remarks It is now clear that in steady state conditions, members of chemokine family play a central role in regulating hematopoiesis. They appear to be central for the maintenance of the hematopoietic niche inducing both the retention and the quiescence of HSCs. In particular, the CXC chemokines CXCL12 and CXCL4 retain the progenitors inside the niche, while the CXCR2 ligands CXCL2 and CXCL8 help keep the quiescent state of HSCs. On the contrary, many CC chemokines have specific inhibitory effects on the myeloid lineage and, at the same time, they are strong inducers of HPC mobilization. In this intricate picture (Fig. 1) many informations are still lacking and a deeper investigation of the system is required. Indeed, selective interference with these chemokines and chemokine receptors could have important clinical implications for the treatment of many diseases and give rise to new treatment modalities. Acknowledgements This study was supported by grants of the Italian Association for Cancer Research, Italy (AIRC IG 15438 and 20269). The authors declare no competing financial interests. References [1] K. Akashi, D. Traver, T. Miyamoto, I.L. Weissman, A clonogenic common myeloid progenitor that gives rise to all myeloid lineages, Nature 404 (2000) 193–197. 79 Cytokine 109 (2018) 76–80 O. Bonavita et al. [20] G.M. Crane, E. Jeffery, S.J. Morrison, Adult haematopoietic stem cell niches, Nat. Rev. Immunol. 17 (2017) 573–590. [21] D.R. Crosslin, A. Mcdavid, N. Weston, X. Zheng, E. Hart, M. De Andrade, I.J. Kullo, C.A. Mccarty, K.F. Doheny, E. Pugh, A. Kho, M.G. Hayes, M.D. Ritchie, A. Saip, D.C. Crawford, P.K. Crane, K. Newton, D.S. Carrell, C.J. Gallego, M.A. Nalls, R. Li, D.B. Mirel, A. Crenshaw, D.J. Couper, T. Tanaka, F.J. Van Rooij, M.H. Chen, A.V. Smith, N.A. Zakai, Q. Yango, M. Garcia, Y. Liu, T. Lumley, A.R. Folsom, A.P. Reiner, J.F. Felix, A. Dehghan, J.G. Wilson, J.C. Bis, C.S. Fox, N.L. Glazer, L.A. Cupples, J. Coresh, G. Eiriksdottir, V. Gudnason, S. Bandinelli, T.M. Frayling, A. Chakravarti, C.M. Van Duijn, D. Melzer, D. Levy, E. Boerwinkle, A.B. Singleton, D.G. Hernandez, D.L. Longo, J.C. Witteman, B.M. Psaty, L. Ferrucci, T.B. Harris, C.J. O’donnell, S.K. Ganesh, C.H.W. Group, E.B. Larson, C.S. Carlson, G.P. Jarvik, R. Electronic Medical, N. Genomics, Genetic variation associated with circulating monocyte count in the eMERGE Network, Hum. Mol. Genet. 22 (2013) 2119–2127. [22] J.F. Dipersio, G.L. Uy, U. Yasothan, P. Kirkpatrick, Plerixafor, Nat. Rev. Drug Discov. 8 (2009) 105–106. [23] J. Duchene, I. Novitzky-Basso, A. Thiriot, M. Casanova-Acebes, M. Bianchini, S.L. Etheridge, E. Hub, K. Nitz, K. Artinger, K. Eller, J. Caamano, T. Rulicke, P. Moss, R.T.A. Megens, U.H. Von Andrian, A. Hidalgo, C. Weber, A. Rot, Atypical chemokine receptor 1 on nucleated erythroid cells regulates hematopoiesis, Nat. Immunol. 18 (2017) 753–761. [24] A.Z. Dudek, I. Nesmelova, K. Mayo, C.M. Verfaillie, S. Pitchford, A. Slungaard, Platelet factor 4 promotes adhesion of hematopoietic progenitor cells and binds IL8: novel mechanisms for modulation of hematopoiesis, Blood 101 (2003) 4687–4694. [25] K.J. Eash, A.M. Greenbaum, P.K. Gopalan, D.C. Link, CXCR2 and CXCR4 antagonistically regulate neutrophil trafficking from murine bone marrow, J. Clin. Invest. 120 (2010) 2423–2431. [26] A.V. Ergen, N.C. Boles, M.A. Goodell, Rantes/Ccl5 influences hematopoietic stem cell subtypes and causes myeloid skewing, Blood 119 (2012) 2500–2509. [27] N. Fujimura, B. Xu, J. Dalman, H. Deng, K. Aoyama, R.L. Dalman, CCR2 inhibition sequesters multiple subsets of leukocytes in the bone marrow, Sci. Rep. 5 (2015) 11664. [28] G.J. Graham, E.G. Wright, R. Hewick, S.D. Wolpe, N.M. Wilkie, D. Donaldson, S. Lorimore, I.B. Pragnell, Identification and characterization of an inhibitor of haemopoietic stem cell proliferation, Nature 344 (1990) 442–444. [29] S. Iida, T. Kohro, T. Kodama, S. Nagata, R. Fukunaga, Identification of CCR2, flotillin, and gp49B genes as new G-CSF targets during neutrophilic differentiation, J. Leukoc. Biol. 78 (2005) 481–490. [30] D. Karpova, H. Bonig, Concise review: CXCR4/CXCL12 signaling in immature hematopoiesis-lessons from pharmacological and genetic models, Stem Cells 33 (2015) 2391–2399. [31] T. Kawai, H.L. Malech, WHIM syndrome: congenital immune deficiency disease, Curr. Opin. Hematol. 16 (2009) 20–26. [32] M. Kondo, A.J. Wagers, M.G. Manz, S.S. Prohaska, D.C. Scherer, G.F. Beilhack, J.A. Shizuru, I.L. Weissman, Biology of hematopoietic stem cells and progenitors: implications for clinical application, Annu. Rev. Immunol. 21 (2003) 759–806. [33] M. Kondo, I.L. Weissman, K. Akashi, Identification of clonogenic common lymphoid progenitors in mouse bone marrow, Cell 91 (1997) 661–672. [34] Y. Le, Y. Zhou, P. Iribarren, J. Wang, Chemokines and chemokine receptors: their manifold roles in homeostasis and disease, Cell Mol. Immunol. 1 (2004) 95–104. [35] A.M. Lichanska, D.A. Hume, Origins and functions of phagocytes in the embryo, Exp. Hematol. 28 (2000) 601–611. [36] M. Locati, A. Mantovani, R. Bonecchi, Atypical matters in myeloid differentiation, Nat. Immunol. 18 (2017) 711–712. [37] B.I. Lord, T.M. Dexter, J.M. Clements, M.A. Hunter, A.J. Gearing, Macrophage-inflammatory protein protects multipotent hematopoietic cells from the cytotoxic effects of hydroxyurea in vivo, Blood 79 (1992) 2605–2609. [38] B.I. Lord, L.B. Woolford, L.M. Wood, L.G. Czaplewski, M. Mccourt, M.G. Hunter, R.M. Edwards, Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein-1 alpha, Blood 85 (1995) 3412–3415. [39] Q. Ma, D. Jones, P.R. Borghesani, R.A. Segal, T. Nagasawa, T. Kishimoto, R.T. Bronson, T.A. Springer, Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4- and SDF-1-deficient mice, Proc. Natl. Acad. Sci. U.S.A. 95 (1998) 9448–9453. [40] A. Mantovani, R. Bonecchi, M. Locati, Tuning inflammation and immunity by chemokine sequestration: decoys and more, Nat. Rev. Immunol. 6 (2006) 907–918. [41] M.G. Manz, S. Boettcher, Emergency granulopoiesis, Nat. Rev. Immunol. 14 (2014) 302–314. [42] M. Massara, O. Bonavita, B. Savino, N. Caronni, M. Sironi, V. Mollica Poeta, E. Setten, C. Recordati, L. Crisafulli, F. Ficara, A. Mantovani, M. Locati, R. Bonecchi, ACKR2 in hematopoietic precursor as a checkpoint of neutrophil release and antimetastatic activity, Nat. Commun. (2018), http://dx.doi.org/10.1038/s41467-01803080-8. [43] D.H. Mcdermott, J.L. Gao, Q. Liu, M. Siwicki, C. Martens, P. Jacobs, D. Velez, E. Yim, C.R. Bryke, N. Hsu, Z. Dai, M.M. Marquesen, E. Stregevsky, N. Kwatemaa, [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] 80 N. Theobald, D.A. Long Priel, S. Pittaluga, M.A. Raffeld, K.R. Calvo, I. Maric, R. Desmond, K.L. Holmes, D.B. Kuhns, K. Balabanian, F. Bachelerie, S.F. Porcella, H.L. Malech, P.M. Murphy, Chromothriptic cure of WHIM syndrome, Cell 160 (2015) 686–699. A. Mendelson, P.S. Frenette, Hematopoietic stem cell niche maintenance during homeostasis and regeneration, Nat. Med. 20 (2014) 833–846. S. Messina-Graham, H. Broxmeyer, SDF-1/CXCL12 modulates mitochondrial respiration of immature blood cells in a bi-phasic manner, Blood Cells Mol. Dis. 58 (2016) 13–18. D. Metcalf, Hematopoietic cytokines, Blood 111 (2008) 485–491. P.M. Murphy, The molecular biology of leukocyte chemoattractant receptors, Annu. Rev. Immunol. 12 (1994) 593–633. U. Naumann, E. Cameroni, M. Pruenster, H. Mahabaleshwar, E. Raz, H.G. Zerwes, A. Rot, M. Thelen, CXCR7 functions as a scavenger for CXCL12 and CXCL11, PLoS One 5 (2010) e9175. F. Norozi, S. Shahrabi, S. Hajizamani, N. Saki, Regulatory role of megakaryocytes on hematopoietic stem cells quiescence by CXCL4/PF4 in bone marrow niche, Leuk. Res. 48 (2016) 107–112. K. Ottersbach, D.N. Cook, W.A. Kuziel, A. Humbles, B. Lu, C. Gerard, A.E. Proudfoot, G.J. Graham, Macrophage inflammatory protein-1alpha uses a novel receptor for primitive hemopoietic cell inhibition, Blood 98 (2001) 3476–3478. L.M. Pelus, S. Fukuda, Chemokine-mobilized adult stem cells; defining a better hematopoietic graft, Leukemia 22 (2008) 466–473. E.G. Perdiguero, F. Geissmann, The development and maintenance of resident macrophages, Nat. Immunol. 17 (2016) 2–8. S. Reid, A. Ritchie, L. Boring, J. Gosling, S. Cooper, G. Hangoc, I.F. Charo, H.E. Broxmeyer, Enhanced myeloid progenitor cell cycling and apoptosis in mice lacking the chemokine receptor, CCR2, Blood 93 (1999) 1524–1533. B.J. Rollins, Chemokines, Blood 90 (1997) 909–928. N. Sanchez-Sanchez, L. Riol-Blanco, G. De La Rosa, A. Puig-Kroger, J. GarciaBordas, D. Martin, N. Longo, A. Cuadrado, C. Cabanas, A.L. Corbi, P. SanchezMateos, J.L. Rodriguez-Fernandez, Chemokine receptor CCR7 induces intracellular signaling that inhibits apoptosis of mature dendritic cells, Blood 104 (2004) 619–625. B. Savino, M.G. Castor, N. Caronni, A. Sarukhan, A. Anselmo, C. Buracchi, F. Benvenuti, V. Pinho, M.M. Teixeira, A. Mantovani, M. Locati, R. Bonecchi, Control of murine Ly6C(high) monocyte traffic and immunosuppressive activities by atypical chemokine receptor D6, Blood 119 (2012) 5250–5260. Y. Si, C.L. Tsou, K. Croft, I.F. Charo, CCR2 mediates hematopoietic stem and progenitor cell trafficking to sites of inflammation in mice, J. Clin. Invest. 120 (2010) 1192–1203. A. Sinclair, L. Park, M. Shah, M. Drotar, S. Calaminus, L.E. Hopcroft, R. Kinstrie, A.V. Guitart, K. Dunn, S.A. Abraham, O. Sansom, A.M. Michie, L. Machesky, K.R. Kranc, G.J. Graham, F. Pellicano, T.L. Holyoake, CXCR2 and CXCL4 regulate survival and self-renewal of hematopoietic stem/progenitor cells, Blood 128 (2016) 371–383. R.J. Staversky, L. Yang, A.N. Goodman, M.A. Georger, M.W. Becker, L.M. Calvi, B.J. Frisch, CCL3 regulates normal hematopoiesis but is not essential for the maintenance of a long-term engrafting hematopoietic stem cell, Am. Soc. Hematol. (2016). R.M. Strieter, J.A. Belperio, M.D. Burdick, S. Sharma, S.M. Dubinett, M.P. Keane, CXC chemokines: angiogenesis, immunoangiostasis, and metastases in lung cancer, Ann. N.Y. Acad. Sci. 1028 (2004) 351–360. R.M. Strieter, M.D. Burdick, B.N. Gomperts, J.A. Belperio, M.P. Keane, CXC chemokines in angiogenesis, Cytokine Growth Factor Rev. 16 (2005) 593–609. B. Suarez-Alvarez, A. Lopez-Vazquez, C. Lopez-Larrea, Mobilization and homing of hematopoietic stem cells, Adv. Exp. Med. Biol. 741 (2012) 152–170. T. Sugiyama, H. Kohara, M. Noda, T. Nagasawa, Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches, Immunity 25 (2006) 977–988. K. Tachibana, S. Hirota, H. Iizasa, H. Yoshida, K. Kawabata, Y. Kataoka, Y. Kitamura, K. Matsushima, N. Yoshida, S. Nishikawa, T. Kishimoto, T. Nagasawa, The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract, Nature 393 (1998) 591–594. F. Ugarte, E.C. Forsberg, Haematopoietic stem cell niches: new insights inspire new questions, EMBO J. 32 (2013) 2535–2547. S. Yona, K.W. Kim, Y. Wolf, A. Mildner, D. Varol, M. Breker, D. Strauss-Ayali, S. Viukov, M. Guilliams, A. Misharin, D.A. Hume, H. Perlman, B. Malissen, E. Zelzer, S. Jung, Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis, Immunity 38 (2013) 79–91. B.S. Youn, C. Mantel, H.E. Broxmeyer, Chemokines, chemokine receptors and hematopoiesis, Immunol. Rev. 177 (2000) 150–174. Y. Zhang, D. Lv, H.J. Kim, R.A. Kurt, W. Bu, Y. Li, X. Ma, A novel role of hematopoietic CCL5 in promoting triple-negative mammary tumor progression by regulating generation of myeloid-derived suppressor cells, Cell Res. 23 (2013) 394–408.
