Chemorepulsion

{{short description|Directional movement of a cell away from a substance}} '''Chemorepulsion''' is the directional movement of a cell away from a substance. Of the two directional varieties of chemotaxis, chemoattraction has been studied to a much greater extent. Only recently have the key components of the chemorepulsive pathway been elucidated.<ref name=four>Vianello, F., E. Righi, et al. (2010). Methods for Quantitation of Leukocyte Chemotaxis and Fugetaxis. T-Cell Trafficking. F. M. Marelli-Berg and S. Nourshargh, Humana Press. 616: 115-124.</ref> The exact mechanism is still being investigated, and its constituents are currently being explored as likely candidates for immunotherapies.<ref name = three>IMMUNOLOGY - CHAPTER ONE > INNATE (NON-SPECIFIC) IMMUNITY Gene Mayer, Ph.D. Immunology Section of Microbiology and Immunology On-line. University of South Carolina.</ref>

{| align=right border=1 width=350 cellpadding=2 cellspacing=0 class=toccolours style="margin-left:0.5em;" ! align=center style="background:#CCBBEE" |Cell Migration Glossary |- | • '''Chemotaxis''' Cellular response to an environmental substance with a directional movement. |- | • '''Chemokinesis''' Cellular response to an environmental substance with a random, non-vectorial movement. |- | • '''Chemoattraction''' Directional cell movement ''towards'' a substance |- | • '''Chemorepulsion''' Directional cell movement ''away'' from a substance |- | • '''Chemokines''' Secreted cell-signaling proteins able to induce chemotaxis in nearby cells. |- | • '''Immunorepulsion''' The active movement of ''immune cells'' away from a substance |- |}

== History and etymology == thumb|left|Neutrophils being repelled from a chemokinetic agent

The mechanism of the chemorepulsion of immune cells was first acknowledged by medical researchers at the Massachusetts General Hospital in Boston in early 2002.<ref name="four"/> The phenomenon was originally referred to as "reverse chemotaxis," and later, “fugetaxis” (derived from the Latin words ''fugere'', to flee from; and ''taxis'', movement).<ref name="four"/> For a time, the words were used interchangeably before being replaced almost exclusively by “chemorepulsion.” While "chemorepulsion" applies to all cell types, the term "immunorepulsion" is gaining momentum as a more specific term that only applies to hematopoietic blood cell types that are involved in immune responses. Different cell types to which the term "immunorepulsion" could potentially be applied include: Myeloid lineage cells (monocytes, macrophages, neutrophils, basophils, eosinophils, erythrocytes, platelets, dendritic cells) and Lymphoid lineage cells (T-cells, B-cells, NK-cells).

==Role in physiological processes== The chemorepulsion of immune cells was first postulated ''a priori'' based on the established migratory behavior of cells evidenced in several naturally occurring physiological processes: the development of the Central Nervous System, the establishment of immune-privileged sites, and thymic emigration.

===Central nervous system development=== During the development of the Central Nervous System, chemokinetic agents influence the localization of neuronal cells by either attracting or repelling the growing axon.<ref>{{cite journal|last1=Wu|first1=W|title=Directional guidance of neuronal migration in the olfactory system by the protein slit|journal=Nature|year=1999|volume=400|issue=6742|pages=331–336|doi=10.1038/22477|pmid=10432110|display-authors=1|last2=Rao|first2=Yi|last3=Wu|first3=Wei|last4=Wong|first4=Kit|last5=Chen|first5=Jin-hui|last6=Jiang|first6=Zhi-Hong|last7=Dupuis|first7=Sophie|pmc=2041931|bibcode=1999Natur.400..331W}}</ref> This mechanism of context-dependent bidirectionality serves as a valuable model of chemorepulsion that can be studied ''in vivo''.<ref name="four"/> Additionally, there is growing evidence that chemorepulsion is probably a key mechanism involved in regulating leukocyte motility.<ref>{{cite journal|last=Yoshie|first=O|title=Role of chemokines in trafficking of lymphocytes and dendritic cells|journal=Int. J. Hematol.|year=2000|volume=72|issue=4|pages=399–407|pmid=11197204}}</ref> Many of the chemorepellents that affect neuronal cell migration, including netrins, semaphorins, slit ligands, and ephrins have recently been implicated in the motility of immune cells.<ref name="four"/> For example, the Slit protein that mediates axonal chemorepulsion has also been shown to inhibit the directed migration of leukocytes in response to chemoattractants.<ref>{{cite journal|last1=Wu|first1=J.Y.|title=The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors|journal=Nature|year=2001|volume=410|pages=948–952|doi=10.1038/35073616|pmid=11309622|display-authors=1|last2=Feng|first2=Lili|last3=Park|first3=Hwan-Tae|last4=Havlioglu|first4=Necat|last5=Wen|first5=Leng|last6=Tang|first6=Hao|last7=Bacon|first7=Kevin B.|last8=Jiang|first8=Zhi-Hong|last9=Zhang|first9=Xiao-Chun|issue=6831|pmc=2072862|bibcode=2001Natur.410..948W }}</ref> Other factors might also provide chemorepulsive effects on immune cells, and these inhibitory effects might be regulated by the tissue microenvironment.

===Immune-privileged sites=== Certain body tissues are able to tolerate antigens without an inflammatory immune response.<ref>{{cite journal|last=Streilein|first=JW|title=Immune privilege as the result of local tissue barriers and immunosuppressive microenvironments|journal=Current Opinion in Immunology|year=1993|volume=5|issue=3|pages=428–432|doi=10.1016/0952-7915(93)90064-Y|pmid=8347303}}</ref> Immune privilege is thought to be an evolutionary adaptation to protect the most vital sensory organs and reproductive structures that would be otherwise severely impaired during an inflammatory response.<ref>{{cite journal|last=Streilein|first=JW|title=Tissue barriers, immunosuppressive microenvironments, and privileged sites: the eye's point of view|journal=Reg Immunol|year=1993|volume=5|issue=5|pages=253–268|pmid=8148235}}</ref> Although these locations are often physically isolated or segregated from access by immune cells, there are some functionally significant characteristics of such environments that are unique, and could potentially be replicated to keep immune cells away from targeted areas. Known immunologically privileged sites include the: # Brain and central nervous system # Eyes # Placenta and fetus # Testicles Characteristics that are particular to immune-privileged sites should be seriously considered when investigating candidates for immunorepulsion therapy. These characteristics include: # Low expression of Classical MHC Class IA molecules. # Expression of immunoregulatory Nonclassical MHC Class IB molecules. # Increased expression of surface molecules that inhibit complement activation. # Local production of immunosuppressive cytokines, such as TGF-β # Presence of neuropeptides. # Expression of Fas ligand that controls the entry of Fas-expressing lymphoid cells.

=== Thymic emigration === T-cells are one of the most critical constituents of the adaptive immune system due to their ability to continue developing after activation.<ref>{{cite journal|last1=Metloubian|first1=M.|title=Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1|journal=Nature|year=2004|volume=427|pages=355–360|doi=10.1038/nature02284|display-authors=1|last2=Lo|first2=Charles G.|last3=Cinamon|first3=Guy|last4=Lesneski|first4=Matthew J.|last5=Xu|first5=Ying|last6=Brinkmann|first6=Volker|last7=Allende|first7=Maria L.|last8=Proia|first8=Richard L.|last9=Cyster|first9=Jason G.|issue=6972|pmid=14737169|bibcode=2004Natur.427..355M |s2cid=4371877 }}</ref> To prevent premature instigation, it is necessary for T-cells to mature in an environment completely isolated from any potentially activating factors (antigens, cytokines, steroids, receptor antagonists, adhesion molecules, etc.).<ref>{{cite journal|last1=Ueno|first1=T.|title=Role for CCR7 ligands in the emigration of newly generated T lymphocytes from the neonatal thy mus|journal=Immunity|year=2002|volume=16|pages=205–218|display-authors=1|doi=10.1016/S1074-7613(02)00267-4|pmid=11869682|last2=Hara|first2=K|last3=Willis|first3=MS|last4=Malin|first4=MA|last5=Höpken|first5=UE|last6=Gray|first6=DH|last7=Matsushima|first7=K|last8=Lipp|first8=M|last9=Springer|first9=TA|issue=2|doi-access=free}}</ref> As a result, T-cells are formed in the bone marrow and subsequently migrate to the cortex of the thymus where they can mature in an antigen-free environment. The thymus supports the differentiation of multiple distinct T cell subsets that play unique roles in the immune system. For example, T-helper, T-cytotoxic, T-memory, and T-suppressor cells all develop in the thymus and must leave it to provide their functions elsewhere in the body during an immune response.<ref>{{cite journal|last=Chaffin|first=K.E.|author2=Prelmutter, R.M|title=A pertussis toxin-sensitive process controls thymocyte emigration|journal=Eur. J. Immunol.|year=1991|volume=21|pages=2565–2573|doi=10.1002/eji.1830211038|pmid=1655469|issue=10|s2cid=36339438 }}</ref> ''In vitro'' models of the T-lymphopoiesis system have revealed that the emigration of mature T-cells occurs as a result of immunorepulsion away from a chemokinetic agent generated from within the thymic organ via a G-protein coupled receptor.<ref>{{cite journal|last=Vianello|first=F.|title=A CXCR4-dependent chemorepellent signal contributes to the emigration of mature single-positive CD4 cel.ls from the fetal thymus|journal=Journal of Immunology|year=2005|volume=175|issue=8|pages=5115–5125|display-authors=1|author2=<Please add first missing authors to populate metadata.>|pmid=16210615 | doi = 10.4049/jimmunol.175.8.5115|doi-access=free|hdl=11577/156399|hdl-access=free}}</ref>

== Role in pathological processes ==

===Viral and bacterial immune evasion=== Pathogens have evolved various strategies of evasion to thwart the host’s mobilization of immune cells, some of which are relevant to immunrepulsion.<ref>{{cite journal|last=Howard|first=J|title=Molecular mimicry of the inflammation modulatory proteins (IMPs) of poxviruses: evasion of the inflammatory response to preserve viral habitat|journal=Journal of Leukocyte Biology|year=1998|volume=64|issue=1|pages=68–71|display-authors=1|author2=<Please add first missing authors to populate metadata.>|pmid=9665277|doi=10.1002/jlb.64.1.68|doi-access=free}}</ref> For example, some microbes actively seek out and infect immune-privileged tissues where the immune response is not active.<ref>{{cite journal|last=Farrell|first=HE|author2=Degli-Esposti, Davis-Poynter NJ|title=Cytomegalovirus evasion of natural killer cell responses|journal=Immunological Reviews|year=1999|volume=168|pages=187–197|doi=10.1111/j.1600-065X.1999.tb01293.x|pmid=10399075 |s2cid=38742701 }}</ref> Others produce immunomodulatory proteins that interfere with the host’s normal immune system response.<ref>{{cite journal|last=Murphy|first=PM|title=Molecular piracy of chemokine receptors by herpesviruses|journal=Infect Agents Dis|year=1994|volume=3|issue=2|pages=137–164|pmid=7812652}}</ref> These proteins function by modulating elements of the host: # Complement system and inflammatory response<ref>{{cite journal|last=Kotwal|first=GJ|title=Poxviral mimicry of complement and chemokine system components: what's the end game?|journal=Immunol Today|year=2000|volume=21|issue=5|pages=242–248|doi=10.1016/S0167-5699(00)01606-6|pmid=10782056}}</ref> # Cytokine network<ref>{{cite journal|last1=Moore|first1=PS|title=Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV|journal=Science|year=1996|volume=274|issue=5293|pages=1739–1744|display-authors=1|doi=10.1126/science.274.5293.1739|pmid=8939871|last2=Boshoff|first2=C|last3=Weiss|first3=RA|last4=Chang|first4=Y|bibcode=1996Sci...274.1739M |s2cid=29713179 }}</ref> # Antigen processing and presentation pathway<ref>{{cite journal|last1=Fruh|first1=K|title=A comparison of viral immune escape strategies targeting the MHC class I assembly pathway|journal=Immunol Rev|year=1999|volume=168|pages=157–166|display-authors=1|doi=10.1111/j.1600-065X.1999.tb01290.x|pmid=10399072|last2=Gruhler|first2=A|last3=Krishna|first3=RM|last4=Schoenhals|first4=GJ|s2cid=21017460}}</ref>

Historically, the active sites of immunomodulatory proteins have suggested relevant targets for conventional immunotherapies.<ref>{{cite journal|last1=Milne|first1=RS|title=RANTES binding and down-regulation by a novel human perpesvirus-6 beta chemokine receptor|journal=Journal of Immunology|year=2000|volume=164|issue=5|pages=2396–2404|display-authors=1|pmid=10679075|last2=Mattick|first2=C|last3=Nicholson|first3=L|last4=Devaraj|first4=P|last5=Alcami|first5=A|last6=Gompels|first6=UA|doi=10.4049/jimmunol.164.5.2396|doi-access=free}}</ref> In the current paradigm, these targets also harbor potential for innovative immunorepulsion therapies.<ref name="four"/>

=== Cancer immune evasion === Cancer cells leverage the chemorepulsion of immune cells to evade recognition and destruction by immune cells.<ref>{{cite journal|last1=Nomura|first1=T|title=Enhancement of anti-tumor immunity by tumor cells transfected with the secondary lymphoid tissue chemokine EBI-1-ligand chemokine and stromal cell-derived factor-1 alpha chemokine genes|journal=Int J Cancer|year=2001|volume=91|issue=5|pages=597–606|pmid=11267967|doi=10.1002/1097-0215(200002)9999:9999<::AID-IJC1107>3.0.CO;2-J|display-authors=1|last2=Hasegawa|first2=Hitoshi|last3=Kohno|first3=Masashi|last4=Sasaki|first4=Miho|last5=Fujita|first5=Shigeru|doi-access=}}</ref> Without a targeted immune response, the cancer cells can proliferate and even metastasize. Studies have been conducted to investigate which chemokines are secreted by tumors that allow them to evade response so diligently.<ref>{{cite journal|last1=Rempel|first1=SA|title=Identification and localization of the cytokine SDF1 and its receptor, CXC chemokine receptor 4, to regions of necrosis and angiogenesis in human glioblastoma|journal=Clin Cancer Res|year=2000|volume=6|issue=1|pages=102–111|display-authors=1|pmid=10656438|last2=Dudas|first2=S|last3=Ge|first3=S|last4=Gutiérrez|first4=JA}}</ref> One study showed that high expression of SDF-1 was responsible for the down-regulation of MHC class I molecules, which significantly interferes with tumor antigen recognition.<ref>{{cite journal|last1=Zou|first1=W|title=Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells|journal=Nat Med|year=2001|volume=7|issue=12|pages=1339–1346|pmid=11726975|doi=10.1038/nm1201-1339|display-authors=1|last2=Machelon|first2=Véronique|last3=Coulomb-l'Hermin|first3=Aurore|last4=Borvak|first4=Jozef|last5=Nome|first5=Françoise|last6=Isaeva|first6=Tatyana|last7=Wei|first7=Shuang|last8=Krzysiek|first8=Roman|last9=Durand-Gasselin|first9=Ingrid |s2cid=24369357}}</ref> Further investigations of high SDF-1 activity indicate that tumors eventually establish an immune privileged site through repulsion of tumor-specific lymphocytes.<ref>{{cite journal|last1=Barbero|first1=S|title=Stromal cell-derived factor 1-alpha stimulates human gliblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt|journal=Cancer Res|year=2003|volume=63|issue=8|pages=1969–1974|display-authors=1|pmid=12702590|last2=Bonavia|first2=R|last3=Bajetto|first3=A|last4=Porcile|first4=C|last5=Pirani|first5=P|last6=Ravetti|first6=JL|last7=Zona|first7=GL|last8=Spaziante|first8=R|last9=Florio|first9=T}}</ref>

Potentially clinically relevant cancer chemokines include: # IL-8: Many cancers have been found to produce and express IL-8. Binding of IL-8 to CXCR1 and CXCR2 receptors has been associated with tumor establishment.<ref>{{cite journal|last=Balkwill|first=F|title=Cancer and the chemokine network|journal=Nature Reviews Cancer|year=2004|volume=4|issue=7|pages=540–550|pmid=15229479|doi=10.1038/nrc1388|s2cid=205467365}}</ref> # SDF-1: Other cancers express high levels of SDF-1, which stimulates tumor growth and disrupts normal immune cell trafficking.<ref>{{cite journal|last=Strieter|first=RM|title=Chemokines: not just leukocyte chemoattractants in the promotion of cancer|journal=Nat Immunol|year=2001|volume=2|issue=4|pages=285–286|pmid=11276195|doi=10.1038/86286|doi-access=free}}</ref>

==Pharmacological relevance==

===Inflammation===

thumb|left|Neutrophils are critical constituents of the innate immune system

Inflammation is one of the first responses of the immune system to infection or irritation. The response is stimulated by chemical factors released by injured cells. These chemical factors induce all associated inflammatory symptoms by sensitizing pain receptors, causing vasodilation of the blood vessels at the scene, and attracting phagocytes.<ref name = one>Stvrtinová, Viera; Ján Jakubovský and Ivan Hulín (1995), "Inflammation and Fever from Pathophysiology: Principles of Disease", Computing Centre, Slovak Academy of Sciences: Academic Electronic Press</ref>

Neutrophils are the first to the scene, triggering other parts of the immune system by releasing factors to summon other leukocytes and lymphocytes. Other innate leukocytes include natural killer cells, mast cells, eosinophils, basophils, macrophages, and dendritic cells. These cells function in concert by identifying and eliminating pathogens that might cause infection.<ref name = one/>

As first responders, the innate immune cells cannot afford to be specific, and must respond to foreign substances in a generic way.<ref name = two>Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walters (2002), "Molecular Biology of the Cell; Fourth Edition. New York and London: Garland Science", "{{ISBN|0-8153-3218-1}}".</ref> Neutrophils, for example, contain toxic substances in their granules that kill or hinder the expansion of pathogens. The cells attack pathogens by releasing strong oxidizing agents including hydrogen peroxide, free oxygen radicals, and hypochlorite.<ref name = one/> Although the attack is effective against bacteria and fungi, the response can inadvertently inflict severe damage to the surrounding host tissue. The misregulation of innate immune cells plays a key role in promulgating inflammatory conditions.

Chemorepulsion is currently being explored as a practicable therapy for the prevention or resolution of unwanted inflammatory responses. A chemorepellent functions by conveying chemical signals to immune cells that instruct them to leave or stay away from a targeted area or tissue in order to restore the tissue to a normal state.

===Graft rejections=== The objective of using chemorepulsion therapy in transplantation medicine is to procure sustainable, site-specific unresponsiveness for the prevention of graft rejection.<ref>{{cite journal|last=Head|first=JR|author2=Billingham RE|title=Immunologically privileged sites in transplantation immunology and oncology|journal=Perspect Biol Med|year=1985|volume=29|issue=1|pages=115–131|pmid=3906552|doi=10.1353/pbm.1985.0038|s2cid=35574942 }}</ref> Current therapies achieve rejection control by indiscriminately suppressing the immune response. In this approach, any benefits achieved by immunosuppression are overcome by increasing the patient's risk of deadly, opportunistic infections. If attainable, constitutive expression of chemorepellents by the donor tissue would create an inducible immune-privileged site for the allograft, and would be an effective alternative treatment for graft rejection prevention.<ref>{{cite journal|last=Head|first=JR|author2=Billingham RE|title=Immune privilege in the testis:evaluation of potential local factors for transplantation|journal=Transplantation|year=1985|volume=40|issue=3|pages=269–275|doi=10.1097/00007890-198509000-00010|pmid=3898493|s2cid=40237018 |doi-access=free}}</ref>

==Mechanism== thumb|right| Along the PIP3 gradient, the signaling pathway is highly conserved between ''D.discoideum'' and human neutrophils

Chemorepulsion is enabled by the same gradient-sensing capability that governs chemotaxis. The gradient signal of the chemokinetic agent is received through specific receptors on the cell surface and is transduced through intracellular machinery to generate the directional response. The cell moves up a gradient of a chemoattractant or down a gradient of a chemorepellent. In addition to axon growth cones, the model organism ''Dictyostelium discoideum'' has been instrumental in determining the mechanisms that mediate chemorepulsion and immunorepulsion.<ref>{{cite journal|last1=Manahan|first1=C.L.|title=Chemoattractant signaling in Dictyostelium discoideum|journal=Annu. Rev. Cell Dev. Biol.|year=2004|volume=20|pages=223–253|display-authors=1|doi=10.1146/annurev.cellbio.20.011303.132633|pmid=15473840|last2=Iglesias|first2=PA|last3=Long|first3=Y|last4=Devreotes|first4=PN|s2cid=4656628 |url=http://pdfs.semanticscholar.org/227c/8d969f72064672872dbea2d70a7b5a0397f7.pdf|archive-url=https://web.archive.org/web/20190220021255/http://pdfs.semanticscholar.org/227c/8d969f72064672872dbea2d70a7b5a0397f7.pdf|url-status=dead|archive-date=2019-02-20}}</ref> The mechanisms of gradient-sensing and cell polarization in ''D. discoideum'' are remarkably conserved in human neutrophils.<ref>{{cite journal|last1=Willard|first1=SS.|title=Signaling pathways mediating chemotaxis in the social amoeaba, Dictyostelium discoideum|journal=Eur. J. Cell Biol.|year=2006|volume=85|pages=897–904|doi=10.1016/j.ejcb.2006.06.003|pmid=16962888|last2=Devreotes|first2=PN|issue=9–10}}</ref>

===Bidirectional decisions=== thumb|left|Directional Decision Making Mechanism in a Human Neutrophil

Leukocytes can exhibit active chemorepulsion away from a factor that is normally considered to stimulate chemoattraction depending on the context.<ref>{{cite journal|last=Devreotes|first=P.|author2=Janetopoulos, C.|title=Eukaryotic chemotaxis: distinctions between directional sensing and polarization|journal=J. Biol. Chem.|year=2003|volume=278|pages=20445–20448|doi=10.1074/jbc.R300010200|pmid=12672811|issue=23|doi-access=free}}</ref> For example, lymphocytes can migrate away from a high concentration of the chemokine SDF-1 rather than be attracted by lower concentrations of the same factor. Similar results have been reported for human neutrophils to the chemokine IL-8.<ref>{{cite journal|last1=Tharp|first1=W.G.|title=Neutrophil chemorepulsion in defined interleukin-8 gradients in vitro and in vivo|journal=J. Leukoc. Biol.|year=2006|volume=79|pages=539–554|display-authors=1|pmid=16365152|last2=Yadav|first2=R|last3=Irimia|first3=D|last4=Upadhyaya|first4=A|last5=Samadani|first5=A|last6=Hurtado|first6=O|last7=Liu|first7=SY|last8=Munisamy|first8=S|last9=Brainard|first9=DM|issue=3|doi=10.1189/jlb.0905516|s2cid=1708811 }}</ref> : • The directional decision to move towards or away from a chemokine appears to be determined by: : • Differential receptor occupancy : • Intracellular kinase activation : • Cyclic nucleotide concentrations

===Signaling pathways=== {| align=left border=1 width=350 cellpadding=2 cellspacing=0 class=toccolours style="margin-right:2.0em;" ! align=center style="background:#CCBBEE" |Abbreviations Legend |- | • '''PI3K''' Phosphoinositide 3-kinase |- | • '''PLC''' Phospholipase C |- | • '''cAMP''' Cyclic adenosine monophosphate, a chemoattractant |- | • '''8CPT-cAMP''' 8-para-chlorphenylthio, a chemorepellent |- | • '''IP-3''' Inositol trisphosphate |- | • '''Pt dIns(3,4,5)P3''' Phosphatidylinositol (3,4,5)-triphosphate |- | • '''SDF-1''' Stromal cell-derived factor 1 |- |}

In both ''D. discoideum'' and human neutrophils, there is a reversal of polarity that occurs when converting from a chemoattraction to a chemorepulsion response.<ref>{{cite book|last=Bacon|first=K.B.|chapter=Analysis of signal transduction following lymphocyte activation by chemokines |title=Chemokine Receptors |year=1997|volume=288|pages=340–361|doi=10.1016/S0076-6879(97)88023-8|series=Methods in Enzymology|pmid=9357003 |isbn=978-0-12-182189-0}}</ref> Evidenced chemotaxis models have been observed using cAMP analogs.<ref>{{cite journal|last=Dustin|first=M.L.|author2=Chakrabortk, A.K.|title=Tug of war at the exit door|journal=Immunity|year=2008|pages=15–17 | pmid = 18199414 | pmc = 2719829 | doi = 10.1016/j.immuni.2008.01.001 | volume=28 | issue = 1 }}</ref> During cAMP-mediated chemoattraction, the chemoattractant cAMP acti vates PI3K at the leading edge along with the localized activation of the small GTPases Rac and Cdc42.<ref>{{cite journal|last1=Heit|first1=B.|title=An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients|journal=J. Cell Biol.|year=2002|volume=159|pages=91–102|display-authors=1|doi=10.1083/jcb.200202114|pmid=12370241|last2=Tavener|first2=S|last3=Raharjo|first3=E|last4=Kubes|first4=P|issue=1|pmc=2173486}}</ref> This in turn activates PLC which leads to the generation of IP-3, which results in a loss of PtdIns(4,5)P2 at the leading edge.<ref>{{cite journal|last1=Armengol|first1=MP|title=Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases|journal=Journal of Immunology|volume=170|issue=12|pages=6320–6328|display-authors=1|pmid=12794165|year=2003|last2=Cardoso-Schmidt|first2=CB|last3=Fernández|first3=M|last4=Ferrer|first4=X|last5=Pujol-Borrell|first5=R|last6=Juan|first6=M|doi=10.4049/jimmunol.170.12.6320|doi-access=free}}</ref> The chemorepellent 8CPT-cAMP inhibits PLC activity and thereby increases Ptds(3,4,5)P3 accumulation and activation of PTEN. In this manner, the chemorepellant reverses the polarity of the PtdIns(3,4,5)P3 gradient and induces chemorepulsion. Recent evidence also implicates a role for PI5K and Rho signaling during directional decision making and migration.<ref>{{cite journal|last1=Alblas|first1=J.|title=Activation of RhoA and ROCK are essential for detachment of migrating leukocytes|journal=Mol. Biol. Cell|year=2001|volume=12|pages=2137–2145|display-authors=1|pmid=11452009|last2=Ulfman|first2=L|last3=Hordijk|first3=P|last4=Koenderman|first4=L|issue=7|pmc=55668|doi=10.1091/mbc.12.7.2137}}</ref>

===Inhibitors=== Useful inhibitors have been investigated in T cells. For example, T cell chemoattraction to SDF-1 is inhibited by the tyrosine kinase inhibitors, genistein and herbimycin.<ref>{{cite journal|last1=Pham|first1=!.H.|title=S1P1 receptor signaling overrides retention mediated G alpha i-coupled receptors to promote T cell egress|journal=Immunity|year=2008|volume=28|pages=122–133|display-authors=1|doi=10.1016/j.immuni.2007.11.017|pmid=18164221|last2=Okada|first2=T|last3=Matloubian|first3=M|last4=Lo|first4=CG|last5=Cyster|first5=JG|issue=1|pmc=2691390}}</ref>

== References ==  {{Reflist|2}}

== External links == * [http://www.celtaxsys.com/ Celtaxsys]

Category:Cell movement