Cytokines, Chemokines, Other Growth Factors, and Their Receptors

Introduction

Hematopoiesis is regulated by cytokine-cell and cell-cell interactions. Cytokines are polypeptides secreted by many cell types either constitutively or after induction and are usually classified based on primary structures associated with their receptor extracellular domains. They regulate a large range of biologic functions, including hematopoiesis, immunity, and inflammation. In context of hematopoiesis, they have effects on proliferation, differentiation, survival/cell death (apoptosis), and cell movement/migration/induced mobilization. They can act in a paracrine fashion on closely adjacent cells, cells at a distance in the same tissue area, or other tissue areas sometimes by their movement from one tissue/organ to another tissue/organ. Cytokines can also work in an autocrine fashion. A rigorous definition of autocrine regulation is that the cytokine works within the cell that produces it, and either maintains the cytokine for internal cellular signaling/activity or can release it, upon which it can then act on the same cell that produced and released it. Autocrine regulation is a much-discussed mode of action, especially in leukemia and other cancers, but in reality it is very difficult to prove this concept of a cell. Many papers that have referred to autocrine production/action have not rigorously proven this concept, even in the case of leukemia or other cancers. Paracrine modes of action refer to the situation when proteins are secreted/released by a cell and then act on another cell, which is more easily proven and verified.

To modify an old proverb: “What is forgotten is doomed to be repeated without gain of new knowledge.” Many current investigators do not cite or even know of crucial past efforts in the field of how cytokines, chemokines, and other growth-modulating factors influence hematopoietic stem cell (HSC) and hematopoietic progenitor cell (HPC) cell biology and of hematopoietic cell regulation. Thus they unfortunately lose out on knowledge that could help their research. For this reason, this review references the older, as well as more recent, literature on cytokines/interleukins (ILs)/chemokines, other growth factors, and their effects on cell regulation. Although this includes an extensive list of references, it is not an exhaustive list.

After many years of intensive research going back to at least the 1960s, it is recognized that cytokines are widely pleiotropic, with numerous cases of redundancy in action and with many overlapping functions. In fact, there are few cytokines that have been shown to have only one cell and mode of action, including production/release of other growth modulating factors, and it is likely even these few such cytokines will eventually be shown to be pleiotropic in action/activity. Individual cytokines can act as agents that induce either positive and/or negative effects or, when used in combination, additive to synergistically positive and/or negative effects. These different actions are sometimes dependent on the target cells(s) of action and depend on how they are combined for in vitro and in vivo assessments. It is highly likely that combined effects of cytokines occur with great frequency during in vivo regulatory events and in context of the microenvironment niche in which they are produced/released (e.g., in the bone marrow [BM]). Moreover, a cytokine can induce the production/release of other cytokines that can then produce effects that were originally ascribed to the cytokine that started this cascading set of regulatory events. Only by studying effects of cytokines at the single isolated target cell level, with and without serum/plasma (to eliminate effects of growth modulating factors present in serum/plasma) can one begin to truly understand the initial target cell(s) and the action(s) of the cytokine(s) of interest. Thus reductionist approaches of unraveling cytokine cell action(s) are more frequently used, as is single-cell ribonucleic acid (RNA) sequencing (RNA-seq), which is used to assess intracellular events. However, ultimately, to fully and clearly understand hematopoiesis and its regulation, it is necessary to put data together in a total context of interacting cytokines and target cells to get a more accurate picture of what is happening at a physiologic and pathologic level. This is necessary to better use our knowledge for eventual enhanced clinical efficacy for treatment of both malignant (e.g., leukemia, lymphoma) and nonmalignant (e.g., preleukemia, myelodysplastic syndromes [MDS], and myeloproliferative neoplasms [MPNs]) diseases.

Cytokines act through specific cell surface receptors to activate intracellular events, with some receptors acting in concert with other receptors to elicit their regulatory effects. It is notable that as late as the mid-1970s not much was known about specific growth factors, other than that for erythropoietin (EPO), the red blood cell hormone, which was the first growth factor to be purified. Recombinant growth factors were not yet produced or known. Growth factors were identified by their purported actions present in crude preparations of cell or tissue extracts or in media conditioned by cells or tissues. The biologic activities attributed to these cell/tissue extracts or conditioned media could have been and, in fact, were in many cases due to combinations of proteins, and one had to rule out effects of confounding and contaminating agents such as bacterial lipopolysaccharide (LPS). In fact, this contamination of even “purified” protein products is still a confounding problem because LPS can stimulate release of cytokines. An example of these growth regulatory factors were the terms for these activities: colony-stimulating activity (CSA), colony-inhibiting activity (CIA), or colony-stimulating factor (CSF), even before it was known what these proteins were. Presently, through biochemical purification procedures and then later through recombinant deoxyribonucleic acid (DNA) technology, the proteins from these crude preparations responsible for these biologic activities were found to include, in addition to EPO, the CSFs: granulocyte-macrophage (GM)-CSF (also known as CSF-2), granulocyte (G)-CSF (also known as CSF-3), interleukin-3 (IL-3) (previously termed multi-CSF), macrophage (M)-CSF (also known as CSF-1), and thrombopoietin (TPO). The CIA molecules were later identified as lactoferrin (LF), H-subunit (H)-ferritin, and some of the ILs, interferons (IFNs), tumor necrosis factors (TNFs), transforming growth factors (TGFs), and a large number of other, now well-defined and characterized, proteins. We now know that GM-CSF, G-CSF, IL-3, M-CSF, EPO, TPO, and two potent costimulating molecules, stem cell factor (SCF) and Flt3-ligand (FL), transmit their cascade of intracellular signaling molecules after binding to specific receptors (R). GM-CSFR is: GM-CSF-alpha (α), subunit cluster density (CD)116; G-CSFR is: CSF3R/CD114; IL-3R is: IL-3RA/CD123; M-CSFR is: tyrosine kinase CSF1R/c-FMS/CD115; EPO has two receptors, those on hematopoietic cells and those on other cells ; the TPOR is: myeloproliferative leukemia protein (MPL)/CD110; SCFR is: the tyrosine kinase c-kit/CD117 and is found as both a cell membrane and soluble protein; and FLR is: the tyrosine kinase, Flt3.

Class or type I cytokines (often referred to as hematopoietins) regulate development, differentiation, and activation of hematopoietic and immune cells. Their receptors are type I membrane proteins with an N-terminal extracellular and C-terminal intracellular orientation. Type I cytokine receptors include receptors for CSFs, ILs, EPO, TPO ( Fig. 11.1 ), and hormones such as growth hormone (GH) and leptin.

Class II cytokines consist of type I IFNs, which include 16 members that are produced by almost every nucleated cell, with approximately 20% to 60% sequence identity, including 12 subtypes of IFN-α, IFN-β, IFN-ε, IFN-κ, and IFN-ω. Type I IFNs initiate signaling by binding to the same receptor composed of two subunits called IFNAR1 and IFNAR2. Type II IFN consists of the single IFN-γ, which signals through a heterodimeric receptor composed of IFNGR1 and IFNGR2. Type III IFNs include IFN-λ1 (IL-29), IFN-λ2 (IL-28A), and IFN-λ3 (IL-28B). Some include the IL-10 family of cytokines (IL-10, IL-19, IL-20, IL-22, IL-24, IL-26) within the group of type III IFNs. The type III IFN receptor is composed of IL-10Rβ and IL-28R ( Fig. 11.2 ).

Structural similarities between the various type I cytokines were not immediately recognized. However, cloning of their receptors revealed significant homology in that the extracellular regions contain a common domain with four conserved cysteines (C4) in the N-terminal segment and a tryptophan-serine doublet near the C-terminal end. Mutagenesis studies revealed a structural role for these amino acids in maintaining tertiary receptor structures without being involved in cytokine interactions. A 200-amino-acid region evolutionarily derived from a tandem of two ancestral fibronectin-like domains were named hematopoietin receptor domain or cytokine-binding homology region (CHR) because they mediate interactions with cytokines. α-Receptors of IL-2 and IL-15 of the γc family are atypical cytokine receptors; they do not contain a CHR, but rather they contain sushi domains. Two conserved Box 1/ Box 2 regions are located in the proximal intracytoplasmic segment ( Fig. 11.3 ). By contrast, type II cytokine receptors contain two cysteine doublets (C2-C2) located in the C-terminal end of both fibronectin-derived domains. They retain Box 1/2 regions but lack a tryptophan-serine-x-serine-tryptophan motif. Both types of receptors bind ligands that display common spatial four α-helix bundle organizations; they use intracellular signaling mediators of Janus kinase (JAK) and signal transducer and activator of transcription (STAT) families. Type I and II cytokine receptors represent homogeneous structural groups of proteins. Sequence homology is noted in limited numbers of cases, including for GH/prolactin (PRL) and for the IL-6 families. Evidence of the common derivation of cytokines is observed in a common four-helix bundle structures, in addition to similar intron-exon relationships and clustering observed for certain cytokine genes, such as genes of the IL-4 family. Receptors can be composed of dimers of a single chain G-CSFR, EPO receptor (EPOR), or TPOR (c-MPL) or are heterodimeric with a common signaling subunit and a unique ligand-binding chain. Heterodimeric receptors are grouped into families based on sharing a common β-chain GM-CSFRα, IL-3Rα, IL-5Rα, or sharing a gp130 receptor (IL-6Rα, leukemia inhibitory factor [LIF] receptor β, ciliary neurotrophic factor receptor α [NTFRα], IL-11Rα IL-12R, IL-23R, oncostatin M receptor α) or sharing a common γ-chain (IL-2Rα, IL-2Rα, IL-4Rα, IL-7Rα, IL-9Rα, IL-13Rα, IL-15Rα, and IL-21Rα) (see Fig. 11.1 ).

Cytokines and Their Modifying Influences

Many CSFs have been implicated in the pathobiology of both hematopoietic and nonhematopoietic disorders or have been used after production by recombinant DNA technology to treat patients. Cytokines are involved in regulation of hematopoiesis at the level of HSC, HPC, and more mature blood or other accessory cells. Accessory cells include stromal cells (which are themselves very heterogenous), endothelial cells, cells belonging to lymphoid lineages (T cells, B cells, natural killer [NK] cells, NKT cells), and innate immune cells (monocytes/macrophages, neutrophilic myeloid cells, dendritic cells [DCs]). Cell regulation is not necessarily easily dissectible, but strides have been made in elucidating these intricate cytokine-cell interactions. Cytokine receptor signaling has been reviewed. Cytokines are involved in developmental processes during embryogenesis, through neonatal, and into adult life. They can fight infections and elicit immune responses. Redundancy in cytokine(s), their receptors, and actions are probably nature’s way to protect the body against unwanted insults that may interfere with specific cytokines and their protective actions. ILs and chemokines are part of the cytokine superfamily of molecules. ILs, chemokines, and their receptors are covered in this chapter, as will other biologically active proteins that influence hematopoiesis. Cytokines are secreted by leukocytes, as well as other cells. They act on, but are not limited to, hematopoietic cells to regulate blood cell production; this includes effects on immune cells and during inflammation. Biologically active proteins influence in vitro and in vivo proliferation, differentiation, and survival/apoptosis (programmed cell death) at the level of HSC, HPC, and more mature cells of the hematopoietic system. It is clear that activities of these proteins can be modified by enzymatic cleavage, such as that mediated by dipeptidylpeptidase (DPP) 4 (a.k.a. CD26), and also in context of oxygen tensions that are vastly different in vivo (~1% to 5% O ₂ in BM, and also low in blood and other tissues, from that of the ambient air conditions of ~21% O ₂ in which most investigators have studied the in vitro and ex vivo activities of these growth regulators). These potent cytokines/chemokines/other growth regulators and their receptors are discussed throughout the chapter. It is not possible to truly understand the action(s) of cytokines and other growth-modulating factors in absence of these modulating/modifying influences on cytokine activities.

Importantly, cytokine-cell interactions can become dysregulated and induce or be involved in pathologic situations. Examples of some adverse pathologic effects of cytokines include the “cytokine storm” elicited following chimeric antigen receptor (CAR) T-cell therapy, during inflammation, and after infection with viruses, such as SARS-CoV-2 (see Chapter 26, Chapter 67, Chapter 68, Chapter 79, Chapter 90, Chapter 152 ). Thus cytokine-cell interactions present a “double-edged sword” for both “good” (physiologic) and “bad” (pathologic) effects. Specific information on cytokines, chemokines, iron-binding proteins, other biologically active proteins, and growth regulation and their receptors follows.

Specifics of Growth-Modulating Factors

There are many cytokines, including CSFs, ILs, and chemokines, which are enumerated as follows.

Colony-Stimulating Factors

Much of the original background on CSFs through the mid to late 1980s has been reviewed, but it is important to understand that the purification and respective cloning of the ligands and receptors of GM-CSF, G-CSF, IL-3, M-CSF, EPO, and TPO have led to the preclinical analyses of their biologic activities in vitro and in vivo, and the eventual evaluation of their effects in humans. For example, EPO has been used to enhance erythropoiesis and production of erythrocytes in humans under a variety of clinical scenarios, GM-CSF, G-CSF, and TPO have been used to accelerate production of myeloid cells, and G-CSF has also been used to mobilize HSC and HPC for eventual collection as autologous and allogeneic stem cell grafts.

Interleukins

The IL family of cytokines now includes IL-1 through IL-38/40, with the first IL, IL-1, purified to homogeneity in 1977. Examples of some of the actions of the ILs and the cell(s) that produce them are summarized in Table 11.1 . ILs are placed in different families based on sequence homology, receptor similarities, and their functional activities. Some of the IL receptors are shown in Fig. 11.4 . Many ILs, as do most members of the cytokine family, have redundant activities and have multiple effects on immune cells and hematopoiesis. Reviews on the IL-1, IL-2, IL-6, IL-10, IL-12, and IL-17 families present in-depth information on many of the known IL molecules. Examples of the hematopoietic actions of some of the ILs from our lab and others, such as IL-1, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8 (also known as the chemokine CXCL8), IL-9, IL-10, IL-11, IL-12, IL-17, IL-18, IL-20, IL-21, IL-26, IL-31, IL-32, and IL-33, have been reported. The receptor for IL-33 is known as suppressor of tumorigenesis (ST2) which is primarily elevated during graft-versus-host disease (GVHD) and is a biomarker associated with a poor prognosis. IL-33 signaling is also associated with hematologic malignancies, autoimmune disorders, allergic inflammation, and gastrointestinal cancers. The ILs work in combination with other ILs, as well as other cytokines, to regulate hematopoiesis in an additive to synergistic fashion.

Table 11.1

Interleukins

Interleukin (IL)	Produced By	Actions
IL-1	Macrophages, B cells, endothelium, fibroblasts, astrocytes	Activates lymphocytes, stimulated macrophages; increases leukocyte/endothelial adhesion
IL-2	T cells	T and B cells proliferation and differentiation; activates NK cells antibody production
IL-3	T cells	Acts as a multi-CSF
IL-4	CD4 + T cells (Th2)	Acts on T and B cells
IL-5	CD4 + T cells (Th2)	Activates eosinophils and production of innate immune cells
IL-6	T and B cells, fibroblasts, macrophages	B-cell differentiation
IL-7	BM stromal cells	Acts on pre-B cells and T cells; stimulates B- and T-cell proliferation
IL-8	Monocytes and fibroblasts	Targets include mature myeloid cells
IL-9	Th9, Th2, Th17, Mast, NKT and TREG cells	Enhances survival of T cells and activates mast cells
IL-10	Th2 cells	Primary targets are Th1 cells; down regulates Th17 cells, and inhibits macrophage IL-12 production
IL-11	BM stromal cells and fibroblasts	Actions on hematopoietic progenitors and osteoclasts
IL-12	Monocytes	Induces Th1 cells, and T cells, and NK cell IFN-γ production
IL-13	Th2, NKT, and mast cells	Acts on monocytes, epithelial cells, and B cells
IL-14	T cells	Activates B cell proliferation and inhibits secretion of immunoglobulins
IL-15	Monocytes, epithelium	Acts on T cells and activated B cells
IL-16	CD8 + T cells and eosinophils	CD4 + T-cell chemoattractant
IL-17	Th17 cells	Acts on epithelial and endothelial cells; causes release of cytokines
IL-18	Macrophages	Cofactor in Th1 cell induction; induces IFN-γ and enhances NK cell activation
IL-19	Th2 cells, antiinflammatory molecules	Antiinflammatory molecule involvement
IL-20	Immune cells and activated epithelial cells	Plays a role in cellular communication
IL-21	NK and CD4 + T cells	Acts on innate and adaptive immune cells, and erythroid progenitor cells
IL-22	T cells and other cells in the innate and acquired immunities	Inhibits IL-4 production
IL-23	Macrophages and dendritic cells	Maintenance of IL-17–producing T cells
IL-24	Monocytes and T and B cells	Involved in wound healing and protects against bacterial infections
IL-25	Dendritic cells	Th2 cells and their production of IL-4 and IL-13
IL-26	Th17 cells	Causes IL-10, IL-1β, IL-6, and IL-8 production
IL-27	T cells	Proinflammatory molecule
IL-28	TREGs	Acts on keratinocytes and melanocytes
IL-29	Virus-infected cells, dendritic cells, TREGs	Upregulates viral protective responses
IL-30	Monocytes in response to Toll-like receptor agonists such as bacterial lipopolysaccharides	Acts on many hematopoietic cells
IL-31	Th2 and dendritic cells	Acts as proinflammatory and chemotactic factor
IL-32	NK cells and monocytes	Induces cytokine production (IL-6, IL-1β) and inhibits IL-15 production
IL-33	Mast cells and Th2 cells	Mediates Th2 responses
IL-34	Phagocytes and epithelial cells	Enhances IL-6 production and is involved in differentiation of antigen-presenting cells
IL-35	Regulatory B cells	Immune suppressor
IL-36	Phagocytes	Acts on T and NK cells
IL-37	Phagocytes	Regulates innate immunity and causes immunosuppression
IL-38	Placenta, B cells, etc.	Acts on T cells, inhibits IL-17 and IL-22 production
IL-39	B cells	Acts on differentiation and expansion of neutrophils
IL-40	BM, fetal liver, activated B cells	Involved in development of humoral immune responses

BM , Bone marrow; CSF , colony-stimulating factor; IFN , interferon; NK , natural killer; Th, T helper; TREG, T regulatory.

Chemokines and Chemokine Receptors

Chemokines, originally considered chemotactic cytokines, are a large family of cytokines that usually signal through G protein–coupled heptahelical receptors ( Table 11.2 and Fig. 11.5 ). There is redundancy within the chemokine family, with some chemokines binding multiple chemokine receptors and, in more rare occasions, nonchemokine receptors, and some chemokine receptors binding multiple chemokines. Fig. 11.6 diagrammatically denotes the many functions of chemokines and chemokine receptors. Chemokines can act as monomers but can form homodimers, heterodimers, and higher aggregates. Specific chemokines and their receptors have been implicated in various phases of HSC regulation. They can act as positive and negative regulators of HSC and HPC and have been implicated in the survival, proliferation, and mobilization of these cells. For example, IL-8/CXCL8, which acts through the chemokine receptors CXCR1 and CXCR2, has been implicated not only in the negative regulation of hematopoiesis, but CXCL8 and CXCR2 have been implicated in leukemia/MDS. Interestingly, DEK, a heterochromatin remodeling agent that has cytokine-like activity, can bind and signal through the chemokine receptor CXCR2 and can compete with IL-8/CXCL8, as well as macrophage inflammatory protein (MIP)-2, at the level of CXCR2. Extracellular DEK potently enhances cytokine-induced ex vivo expansion of mouse BM and human cord blood (CB) HSCs, plus has other effects. Another well-recognized chemokine and its receptor is SDF-1/CXCL12 and CXCR4, respectively. stromal cell-derived factor (SDF)-1/CXCL12 is involved in normal and leukemic HSC/HPC survival, proliferation, chemotaxis, migration, and mobilization. SDF-1/CXCL12 also binds to CXCR7, but CXCR4 appears to be the main hematopoietic signaling receptor for SDF-1/CXCL12. Blocking of CXCR4 by the CXCR4 antagonist, AMD3100/plerixafor, has been used to induce the mobilization of peripheral blood HSC and HPC and to synergize with G-CSF in this mobilization. Chemokines are affected by a number of posttranslational modifications, including by DPP4, which is discussed later in this review. They are inducible by several different stimuli and are involved and are players in response to infection and inflammation. There are also viral genes that encode chemokine receptors. Chemokine receptors can also regulate infectivity to viruses. For example, individuals with specific mutations in CXCR5 are immune or less susceptible to infection with human immunodeficiency virus (HIV), but thus far only very few patients with HIV have been “cured” by allogeneic stem cell transplantation using donor cells from stem cell donors with this specific variant of mutated CXCR5.

Table 11.2

Chemokines

Adapted from R&D Systems Inc, Minneapolis MN. https://www.rndsystems.com/resources/technical-information/chemokine-nomenclature. Used with the permission of Bio-Techne.

Name(s)	Human Receptor(s)	Mouse Receptor(s)
CCL Chemokines
CCL1 (I-309)	CCR8, DARC	CCR8
CCL2 (MCP-1, MCAF)	CCR2, CCR4, CCR11, D6, DARC	CCR2, CCR4, D6, DARC (JE = mouse ligand along with MCP-1)
CCL3 (MIP-1α, LD78)	CCR1, CCR4, CCR5, D6	CCR1, CCR4, CCR5, D6
CCL3L1 (LD78β)	CCR1, CCR3, CCR5, D6	___
CCL3L3 (LD78β)	CCR1, CCR3, CCR5	___
CCL4 (MIP-1β)	CCR1, CCR5, CCR8, D6	CCR5, CCR1
CCL4L1	CCR1, CCR5	___
CCL5 (RANTES)	CCR1, CCR3, CCR5, CCR4, D6, DARC	CCR1, CCR3, CCR5, CCR4
CCL6	___	CCR1
CCL7 (MCP-3)	CCR1, CCR2, CCR3, D6, DARC	CCR1, CCR2, CCR3
CCL8 (MCP-2)	CCR1, CCR2, CCR5, CCR3, CCR11, D6, DARC	___
CCL9/10 (MIP-1γ)	___	CCR1, CCR3
CCL11 (Eotaxin)	CCR3, CCR5, D6, DARC	CCR3, DARC
CCL12 (MCP-5)	___	CCR2
CCL13 (MCP-4, CKβ)	CCR2, CCR3, CCR1, CCR5, CCR11, D6, DARC	___
CCL14 (HCC-1, MCIF, CKβ1)	CCR1, CCR3, CCR5, D6, DARC	___
CCL15 (MIP-1δ, MIP-1γ, LKN-1, MIP-5)	CCR1, CCR3	CCR1, CCR3
CCL16 (HCC-4, LEC, LMC)	CCR1, CCR2, CCR5, CCR8, H4, DARC	___
CCL17 (TARC)	CCR4, CCR8, D6, DARC	CCR4
CCL18 (PARC, CKβ7, MIP-4)	PITPNM3, CCR8, DARC	___
CCL19 (MIP-3β, ELC, Exodus-3)	CCR7, CCR11	CCR7, CCR11
CCL20 (MIP-3α, LARC, Exodus-1)	CCR6	CCR6
CCL21 (6CKine, Exodus-2)	CCR7, CCR11	CCR7, CCR11
CCL22 (MDC)	CCR4, D6	CCR4
CCL23 (MPIF, CKβ8, MIP3)	CCR1	CCR1
CCL24 (Eotaxin-2)	CCR3	CCR3
CCL25 (TECK, CKβ15)	CCR9, CCR11	CCR9, CCR11
CCL26 (Eotaxin-3, MIP-4α)	CCR3, CX 3 CR1	___
CCL27 (CTACK, PESKY, Eskine)	CCR10	CCR10
CCL28 (MEK)	CCR3, CCR10	CCR10
CXC Chemokines
CXCL1 (GRO-α, GRO1, NAP3 DCIP-1)	CXCR2, DARC	CXCR2, DARC
CXCL2 (GRO-β, MIP-2α, GRO2, MIP-2)	CXCR2, DARC	CXCR2, DARC
CXCL3 (GRO-γ, MIP-2β, KC)	CXCR3B, CXCR3, DARC	___
CXCL4L1 (PF4V1)	CXCR3B, CXCR3	CXCR3
CXCL5 (ENA-78)	CXCR2, DARC	___
CXCL6 (GCP-2)	CXCR1, CXCR2, DARC	CXCR1, CXCR2, DARC
CXCL7 (NAP2)	CXCR1, CXCR2	CXCR1, CXCR2
CXCL8 (IL-8, NAP-1, GCP-1)	CXCR1, CXCR2, DARC	___
CXCL9 (MIG)	CXCR3, CXCR3B, DARC	CXCR3
CXCL10 (IP-10)	CXCR3, CXCR3B, DARC	CXCR3
CXCL11 (I-TAC)	CXCR3, CXCR7, CXCR3B, DARC	CXCR3, CXCR7
CXCL12 (SDF-1)	CXCR4, CXCR7	CXCR4, CXCR7
CXCL13 (BCA-1, BLC)	CXCR3, CXCR5, DARC	CXCR5
CXCL14 (BRAK)	Unknown	Unknown
CXCL15 (Lungkine)	___	Unknown
CXCL16 (---)	CXCR6	CXCR6
CXCL17 (DMC)	Unknown	Unknown
LIX (---)	___	CXCR1, CXCR2, DARC
CX3C Chemokines
CX3CL1 (Fractakine/Neurotactin)	CX3CR1	CX3CR1
C Chemokines
XCL1 Lymphotactin, SCM-1α, ATAC)	XCR1	XCR1
XCL2 (SCM-1β)	XCR1	___

The complex network of cytokines and chemokines and their overlapping and diverse effects on a variety of cellular processes is truly incredible and goes beyond regulation of normal cells. Although redundant chemokine/chemokine receptor interactions are likely the body’s way to protect itself, this “protection” can elicit serious consequences. Many chemokines and their receptors are part of the triggered cytokine release syndrome (CRS), which represents a side effect following CAR-T-cell therapy and viral infections, such as that induced by SARS-Cov-2 during COVID-19 infections. These events lead to excessive elaboration of chemokines and other cytokines and their receptors, representing the “double-edged sword” discussed earlier in terms of health benefits and disease-related problems. Greater knowledge of the production and actions of chemokines, and their intracellular signaling cascades that are induced through chemokine and cytokine receptors, is crucial for future benefits for normal cell regulation and their modification and to dampen their adverse effects during disease.