Dysregulated autotaxin expression by T cells in multiple sclerosis
Copyright © 2023. Published by Elsevier B.V..
Multiple sclerosis (MS) is a demyelinating disease characterized by infiltration of autoreactive T cells into the central nervous system (CNS). In order to understand how activated, autoreactive T cells are able to cross the blood brain barrier, the unique molecular characteristics of pathogenic T cells need to be more thoroughly examined. In previous work, our laboratory found autotaxin (ATX) to be upregulated by activated autoreactive T cells in the mouse model of MS. ATX is a secreted glycoprotein that promotes T cell chemokinesis and transmigration through catalysis of lysophoshphatidic acid (LPA). ATX is elevated in the serum of MS patients during active disease phases, and we previously found that inhibiting ATX decreases severity of neurological deficits in the mouse model. In this study, ATX expression was found to be lower in MS patient immune cells during rest, but significantly increased during early activation in a manner not seen in healthy controls. The ribosomal binding protein HuR, which stabilizes ATX mRNA, was also increased in MS patients in a similar pattern to that of ATX, suggesting it may be helping regulate ATX levels after activation. The proinflammatory cytokine interleukin-23 (IL-23) was shown to induce prolonged ATX expression in MS patient Th1 and Th17 cells. Finally, through ChIP, re-ChIP analysis, we show that IL-23 may be signaling through pSTAT3/pSTAT4 heterodimers to induce expression of ATX. Taken together, these findings elucidate cell types that may be contributing to elevated serum ATX levels in MS patients and identify potential drivers of sustained expression in encephalitogenic T cells.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:387 |
---|---|
Enthalten in: |
Journal of neuroimmunology - 387(2024) vom: 15. Feb., Seite 578282 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Petersen-Cherubini, Cora L [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 14.02.2024 Date Revised 21.03.2024 published: Print-Electronic Citation Status MEDLINE |
---|
doi: |
10.1016/j.jneuroim.2023.578282 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM36674559X |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM36674559X | ||
003 | DE-627 | ||
005 | 20240321235827.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240108s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1016/j.jneuroim.2023.578282 |2 doi | |
028 | 5 | 2 | |a pubmed24n1338.xml |
035 | |a (DE-627)NLM36674559X | ||
035 | |a (NLM)38183947 | ||
035 | |a (PII)S0165-5728(23)00268-0 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Petersen-Cherubini, Cora L |e verfasserin |4 aut | |
245 | 1 | 0 | |a Dysregulated autotaxin expression by T cells in multiple sclerosis |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 14.02.2024 | ||
500 | |a Date Revised 21.03.2024 | ||
500 | |a published: Print-Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Copyright © 2023. Published by Elsevier B.V. | ||
520 | |a Multiple sclerosis (MS) is a demyelinating disease characterized by infiltration of autoreactive T cells into the central nervous system (CNS). In order to understand how activated, autoreactive T cells are able to cross the blood brain barrier, the unique molecular characteristics of pathogenic T cells need to be more thoroughly examined. In previous work, our laboratory found autotaxin (ATX) to be upregulated by activated autoreactive T cells in the mouse model of MS. ATX is a secreted glycoprotein that promotes T cell chemokinesis and transmigration through catalysis of lysophoshphatidic acid (LPA). ATX is elevated in the serum of MS patients during active disease phases, and we previously found that inhibiting ATX decreases severity of neurological deficits in the mouse model. In this study, ATX expression was found to be lower in MS patient immune cells during rest, but significantly increased during early activation in a manner not seen in healthy controls. The ribosomal binding protein HuR, which stabilizes ATX mRNA, was also increased in MS patients in a similar pattern to that of ATX, suggesting it may be helping regulate ATX levels after activation. The proinflammatory cytokine interleukin-23 (IL-23) was shown to induce prolonged ATX expression in MS patient Th1 and Th17 cells. Finally, through ChIP, re-ChIP analysis, we show that IL-23 may be signaling through pSTAT3/pSTAT4 heterodimers to induce expression of ATX. Taken together, these findings elucidate cell types that may be contributing to elevated serum ATX levels in MS patients and identify potential drivers of sustained expression in encephalitogenic T cells | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a Autotaxin | |
650 | 4 | |a Autotaxin/LPA axis | |
650 | 4 | |a CD4 T cells | |
650 | 4 | |a CNS autoimmunity | |
650 | 4 | |a Multiple sclerosis | |
650 | 7 | |a Phosphoric Diester Hydrolases |2 NLM | |
650 | 7 | |a EC 3.1.4.- |2 NLM | |
650 | 7 | |a Cytokines |2 NLM | |
650 | 7 | |a Interleukin-23 |2 NLM | |
650 | 7 | |a Lysophospholipids |2 NLM | |
700 | 1 | |a Liu, Yue |e verfasserin |4 aut | |
700 | 1 | |a Deffenbaugh, Joshua L |e verfasserin |4 aut | |
700 | 1 | |a Murphy, Shawn P |e verfasserin |4 aut | |
700 | 1 | |a Xin, Matthew |e verfasserin |4 aut | |
700 | 1 | |a Rau, Christina N |e verfasserin |4 aut | |
700 | 1 | |a Yang, Yuhong |e verfasserin |4 aut | |
700 | 1 | |a Lovett-Racke, Amy E |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Journal of neuroimmunology |d 1985 |g 387(2024) vom: 15. Feb., Seite 578282 |w (DE-627)NLM012614181 |x 1872-8421 |7 nnns |
773 | 1 | 8 | |g volume:387 |g year:2024 |g day:15 |g month:02 |g pages:578282 |
856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.jneuroim.2023.578282 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 387 |j 2024 |b 15 |c 02 |h 578282 |