PMID- 30578562
OWN - NLM
STAT- MEDLINE
DCOM- 20190613
LR  - 20190613
IS  - 1098-1136 (Electronic)
IS  - 0894-1491 (Linking)
VI  - 67
IP  - 3
DP  - 2019 Mar
TI  - Spinal IL-36gamma/IL-36R participates in the maintenance of chronic inflammatory pain 
      through astroglial JNK pathway.
PG  - 438-451
LID - 10.1002/glia.23552 [doi]
AB  - Emerging evidence indicates that spinal neuroinflammation contributes to the 
      maintenance of chronic inflammatory pain. IL-36, as a novel member of the 
      interleukin (IL)-1 super-family cytokines, plays an important role in 
      inflammatory responses. The present study aimed to investigate the role of spinal 
      IL-36 and IL-36 receptor (IL-36R) signaling in the pathology of chronic 
      inflammatory pain. IL-36gamma and IL-36R, but not IL-36alpha and IL-36beta, were 
      persistently upregulated in the spinal cord of mice with intraplantar injections 
      of complete Freund's adjuvant (CFA). Intrathecal administration of both IL-36R 
      antagonist (IL-36Ra) and IL-36gamma siRNA significantly attenuated CFA-induced 
      chronic inflammatory pain behaviors. Furthermore, CFA-induced IL-36gamma expression 
      was mainly observed in spinal neurons whereas IL-36R was primarily expressed in 
      spinal astrocytes. Additionally, the intrathecal injection of IL-36gamma was 
      sufficient to induce pain hypersensitivity and astrocyte activation in naive 
      mice, and these effects could be inhibited by blocking c-Jun N-terminal kinase 
      (JNK) phosphorylation. In vitro experiments also demonstrated that the IL-36gamma 
      could induce astrocytic JNK activation and inflammatory cytokines release, which 
      was mediated by IL-36R. Finally, intrathecal injection of IL-36gamma-activated 
      astrocytes in a pJNK-dependent manner induced mechanical allodynia and thermal 
      hyperalgesia in naive mice. Collectively, these findings reveal that the 
      neuronal/astrocytic interaction in the spinal cord by which neuronally produced 
      IL-36gamma activates astrocytes via IL-36R-mediated JNK pathway is crucial for the 
      maintenance of chronic inflammatory pain. Thus, IL-36gamma/IL-36R-mediated astrocyte 
      signaling may be a suitable therapeutic target for chronic inflammatory pain.
CI  - (c) 2018 Wiley Periodicals, Inc.
FAU - Li, Qian
AU  - Li Q
AD  - Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong 
      University, Shanghai, China.
FAU - Liu, Shenbin
AU  - Liu S
AD  - Department of Integrative Medicine and Neurobiology, State Key Laboratory of 
      Medical Neurobiology, School of Basic Medical Science, Institutes of Brain 
      Science, Collaborative Innovation Center for Brain Science, Fudan Institutes of 
      Integrative Medicine, Fudan University, Shanghai, China.
FAU - Li, Lingling
AU  - Li L
AD  - Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong 
      University, Shanghai, China.
FAU - Ji, Xiaoli
AU  - Ji X
AD  - Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong 
      University, Shanghai, China.
FAU - Wang, Min
AU  - Wang M
AD  - Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong 
      University, Shanghai, China.
FAU - Zhou, Junmei
AU  - Zhou J
AUID- ORCID: 0000-0002-4333-5033
AD  - Department of Central Laboratory, Shanghai Children's Hospital, Shanghai Jiaotong 
      University, Shanghai, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20181221
PL  - United States
TA  - Glia
JT  - Glia
JID - 8806785
RN  - 0 (IL1F9 protein, mouse)
RN  - 0 (IL36RN protein, human)
RN  - 0 (Interleukin-1)
RN  - 0 (Interleukins)
RN  - 0 (Receptors, Interleukin-1)
RN  - 0 (interleukin-36 receptor, mouse)
RN  - 9007-81-2 (Freund's Adjuvant)
SB  - IM
MH  - Animals
MH  - Astrocytes/drug effects/*metabolism
MH  - Disease Models, Animal
MH  - Freund's Adjuvant
MH  - Hyperalgesia/metabolism
MH  - Inflammation/chemically induced/*metabolism
MH  - Interleukin-1/*metabolism
MH  - Interleukins/pharmacology
MH  - MAP Kinase Signaling System/*physiology
MH  - Mice
MH  - Neurons/drug effects/metabolism
MH  - Pain/chemically induced/*metabolism
MH  - Pain Measurement
MH  - Phosphorylation
MH  - Receptors, Interleukin-1/*metabolism
OTO - NOTNLM
OT  - IL-36
OT  - IL-36 receptor
OT  - astrocyte
OT  - inflammatory pain
OT  - mice
EDAT- 2018/12/24 06:00
MHDA- 2019/06/14 06:00
CRDT- 2018/12/23 06:00
PHST- 2018/05/01 00:00 [received]
PHST- 2018/09/22 00:00 [revised]
PHST- 2018/10/01 00:00 [accepted]
PHST- 2018/12/24 06:00 [pubmed]
PHST- 2019/06/14 06:00 [medline]
PHST- 2018/12/23 06:00 [entrez]
AID - 10.1002/glia.23552 [doi]
PST - ppublish
SO  - Glia. 2019 Mar;67(3):438-451. doi: 10.1002/glia.23552. Epub 2018 Dec 21.