Gianni Marone
University of Naples
Federico II, Italy
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TABLE 1
Nomenclature of Chemokine Families and Paired Receptors Standard name Chromo- some Human ligand Chemokine receptor(s) Standard name Chromo- some Human ligand Chemokine receptor(s) CxC-chemokines CCL3L3 17q21.1 LD78β CCR1, CCR5 (CD195) CXCL1 4q21.1 GROα/MGSAα CXCR2>CXCR1 CCL4 17q12 MIP-1β CCR5 (CD195) CXCL2 4q21.1 GROβ/MIP-2α CXCR2 CCL4L1 17q12 LAG-1 CCR5 (CD195) CXCL3 4q21.1 GROβ/MIP-2β CXCR2 CCL4L2 17q12 CCL4L CCR5 (CD195)
CXCL4 4q21.1 Platelet Factor-4 CXCR3 (CD183) CCL5 17q12 RANTES CCR1, CCR3, CCR5 (CD195) CXCL4L1 4q12-q21 PF4V1 CXCR3 (CD183) CCL6* CXCL5 4q21.1 ENA-78 CXCR2 CCL7 17q11.2 MCP-3 CCR1, CCR2, CCR3 CXCL6 4q21.1 GCP-2 CXCR1,CXCR2 CCL8 17q11.2 MCP-2 CCR3, CCR5 (CD195) CXCL7 4q21.1 NAP-2 CXCR2 CCL9* CXCL8 4q21.1 IL-8 CXCR1,CXCR2 CCL10* CXCL9 4q21.1 MIG CXCR3 (CD183) CCL11 17q11.2 Eotaxin CCR3 CXCL10 4q21.1 IP-10 CXCR3 (CD183) CCL12* CXCL11 4q21.1 I-TAC CXCR3 (CD183) CCL13 17q11.2 MCP-4 CCR2, CCR3 CXCL12 10q11.21 SDF-1α/β CXCR4 (CD184) CCL14 17q12 HCC-1 CCR1, CCR5 (CD195) CXCL13 4q21.1 BCLC CXCR5 CCL15 17q12 HCC-2 CCR1, CCR3 CXCL14 5q31.1 BRAK CXCR4 (CD184) CCL16 17q12 HCC-4 CCR1, CCR2 CXCL15* CCL17 16q13 TARC CCR4
CXCL16 17p13 SR-PSOX CXCR6 CCL18 17q12 PARC Unknown
CXCL17 19q13.2 DMC Unknown CCL19 9p13.3 ELC CCR7 (CD197)
C-chemokines CCL20 2q36.3 MIP-3α, LARC CCR6
XCL1 1q24.2 Lymphotactin/α XCR1 CCL21 9p13.3 SLC CCR7 (CD197) XCL2 1q24.2 Lymphotactin/β XCR1 CCL22 16q13 MDC CCR4 Cx3C-chemokines CCL23 17q12 MPIF-1 CCR1 CX3CL1 16q13 Fractalkine CX3CR1 CCL24 7q11.23 Eotaxin-2 CCR3 CC-chemokines CCL25 19p13.3 TECK CCR9 CCL1 17q11.2 I-309 CCR3 CCL26 7q11.23 Eotaxin-3 CCR3 CCL2 17q11.2 MCP-1 CCR2 CCL27 9p13.3 CTACK CCR10 CCL3 17q12 MIP-1α CCR1, CCR5 (CD195) CCL28 5p12 MEC CCR3/CCR10 CCL3L1 17q21.1 LD78β CCR1, CCR5 (CD195)
*No human ortholog described
Modified from Bachelerie et al., Pharmacol. Rev. 66: 1-79, 2014, with update on Pubmed Library and Genebank.
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Figure 1 . The association of CC and CXC chemokines (CCL and CXCL indicated by outer arrows, member numbers listed in the outer gray circle) and their receptors (listed in pink circle below ) to a selection of diseases, gained from animal models and from data obtained in human samples and in clinical trials. Abbreviations: Sep, Sepsis; RA, Rheumatoid
arthritis; T, Transplant; IBD, Inflammatory Bowel Disease; Onc, Oncology; SLE, Systemic Lupus; MS, Multiple Sclerosis; Ath Scl, Atherosclerosis; COPD: Chronic Obstructive Pulmonary Disease; AMD, Acute macular degeneration; NP, Neuropathic pain; Asth, Asthma; At. Derm, Atopic dermatitis; Hep, Hepatitis; Panc, Pancreatitis; Pso, Psoriasis; GVHD,
Graft vs Host disease. (Reprinted with permission from Garin and Proudfoot, Exp. Cell. Res. 317: 602-612, 2011.)
Cell migration and chemokines
the chemokine superfamily. The key role of chemokines in chronic inflammatory diseases is now firm- ly established (Figure 1). In these contexts, the CXC and CC sub- classes, though with overlaps, seg- regate their control over different
cell types, with CXC members act- ing on effector functions relevant in diseases characterized by neu- trophilic, Th1- and Th-17-driven responses, such as COPD, multiple sclerosis, Crohn’s disease and spe- cific phenotypes of severe asthma;
while CC chemokines shape leu- kocyte trafficking and function in Th2-dependent, eosinophil-rich inflammatory processes such as allergic asthma, early-stage atopic dermatitis, eosinophilic gastroin- testinal diseases (Figure 2). Among
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Figure 2 Involvement of chemokines and chemokine receptors in the inflammatory response present in bronchial asthma and COPD . In asthma, dendritic- and epithelial-derived chemokines elicited by the inhaled allergens recruit and activate Th2 cells and eosinophils through CCR4 and CCR3, respectively, contributing to the generation of an IgE-mediated inflam- matory response. In COPD, chemokines released from lung epithelial cells and macrophages following exposure to cigarette smoke and/or pollutants generate a neutrophilic/monocytic-enriched infiltrate driven by Th1/Th17 cells that contributes to the inflammatory response and determins lung structural damage. (Reprinted by permission from Macmillan Publishers Ltd: Nat
Rev Immunol, Barnes PJ, Immunology of asthma and chronic obstructive pulmonary disease, 8,183-192, copyright 2008.)
Asthma
COPD
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the CC chemokines, CCL2/Mono- cyte Chemoattractant Protein-1 (MCP-1) is a non-redundant, po- tent regulator of monocytes, ba- sophils and dendritic cells and par- ticipates to the Th2 polarization of memory T cells. The CX3C and the C subfamilies are represented by a single member, CX3CL1/frac- talkine, which is the only cell mem- brane-associated chemokine, and lymphotactin, respectively.
Chemokines’ range of regulatory competences has been widened over the last decades, as almost all cell types, including structural cells such as fibroblasts, endothe- lial and epithelial cells, as well as tumor cells have been found to express regulated profiles of func- tional chemokine receptors. By regulating cell proliferation, differ- entiation and apoptosis functions, and – either directly or indirectly – controlling angiogenesis and ex- tracellular matrix remodeling, the chemokine system is also central to cancer-related inflammation, angiogenesis, tumor cell survival and invasiveness, and is critically involved in the step-wise process of wound healing.
Inhibition of leukocyte recruit- ment is a major mechanism of glu- cocorticoids’ anti-inflammatory action and a major goal for novel therapies selectively targeting specific recruitment pathways. Antagonism of chemokine-me- diated functions offers major challenges, partly due to member redundancy in each subclass, but mostly to the complexity of the control of their expression, which spans from transcriptional to post- translational and extracellular ma- trix-dependent mechanisms, that are diversely affected in specific disease settings. Antagonism of single chemokine receptors has so far shown only partial success as therapeutic strategy, and is now flanked by research toward more specific downstream regu- latory pathways modulating the chemokine network.
KEY REFERENCES
1. Rot A, von Andrian UH. Chemok- ines in innate and adaptive host de- fense: basic chemokinese grammar for immune cells. Annu Rev Immunol 2004;22:891-928.
2. Luster AD, Alon R, von Andrian UH. Immune cell migration in inflamma-
tion: present and future therapeu- tic targets. Nat Immunol 2005;6: 1182-1190.
3. Charo IF, Ransohoff RM. The many roles of chemokines and chemok- ine receptors in inflammation. N
Engl J Med 2006;354:610-621.
4. Garin A, Proudfoot AE. Chemok- ines as targets for therapy. Exp Cell
Res 2011;317:602-612.
5. Islam SA, Luster AD. T cell homing to epithelial barriers in allergic dis- ease. Nat Med 2012;18:705-715. 6. Fan J, Heller NM, Gorospe M,
Atasoy U, Stellato C. The role of post-transcriptional regulation in chemokine gene expression in in- flammation and allergy. Eur Respir J 2005;26:933-947.
7. Bachelerie F, Ben-Baruch A, Bur- khardt AM, Combadiere C, Farber JM, Graham GJ et al. International Union of Pharmacology. LXXXIX. Update on the extended family of chemokine receptors and introduc- ing a new nomenclature for atypi- cal chemokine receptors. Pharma-
col Rev 2014;66:1-79.
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• The phylogenetically ancient complement activation system is activated in the lungs of asthmatic individuals
• Several environmental triggers of asthma including allergens, air pollutants, cigarette smoke, and viruses activate the complement system and mediate Th2-driven immune responses
• Genetic polymorphisms in the C3 and C3aR1 genes are associated with susceptibility to the development of asthma in children and adults
• Modification of complement activation pathways may provide a novel strategy for the treatment of asthma
Asthma is thought to arise as a result of aberrant T helper type 2 (Th2)-polarized immune respons- es to innocuous environmental al- lergens, however the mechanisms driving these aberrant immune re- sponses remain elusive. As a phy- logenetically ancient immune sys- tem, the complement activation system, is a sophisticated network of soluble and membrane-bound proteins. It has evolved to recog- nize “danger or pattern-associated molecular patterns” expressed by foreign organisms through “hard- wired” pattern recognition recep- tors (PRRs). Activation of these PRRs culminates in the generation of C3 and the production of two pro-inflammatory anaphylatoxins, C3a and C5a, which induce inflam- mation and the membrane attack complex, which lyses foreign cells. The anaphylatoxins C3a and C5a are potent pro-inflammatory me- diators that bind to specific cell surface receptors and regulate many processes observed in asth- ma including leukocyte activation, smooth muscle contraction, and mucus secretion.
Consistent with a role for C3-C3a in asthma, exposure to a variety of environmental triggers of asthma in animal models has been shown