IL-35 alleviates inflammation progression in a rat model of diabetic neuropathic pain via inhibition of JNK signaling

Jiang, Yuling; Wang, Jing; Li, Haiqin; Xia, Liangping

doi:10.1186/s12950-019-0217-z

Cited by 26 publications

(18 citation statements)

References 29 publications

(30 reference statements)

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“…Diabetic mice have been shown to present impaired angiogenesis and recovery from HLI. IL-35 has been reported to inhibit diabetic neuropathic pain ( 80 ). Due to the limited scope of this study, we were unable to include diabetic conditions into our consideration ( 64 ).…”

Section: Discussionmentioning

confidence: 99%

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Sun

Shao

et al. 2020

Front. Immunol.

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Interleukin (IL) 35 is a novel immunosuppressive heterodimeric cytokine in IL-12 family. Whether and how IL-35 regulates ischemia-induced angiogenesis in peripheral artery diseases are unrevealed. To fill this important knowledge gap, we used loss-of-function, gain-of-function, omics data analysis, RNA-Seq, in vivo and in vitro experiments, and we have made the following significant findings: i ) IL-35 and its receptor subunit IL-12RB2, but not IL-6ST, are induced in the muscle after hindlimb ischemia (HLI); ii ) HLI-induced angiogenesis is improved in Il12rb2−/− mice, in ApoE−/−/Il12rb2−/− mice compared to WT and ApoE−/− controls, respectively, where hyperlipidemia inhibits angiogenesis in vivo and in vitro; iii ) IL-35 cytokine injection as a gain-of-function approach delays blood perfusion recovery at day 14 after HLI; iv ) IL-35 spares regenerative angiogenesis at the late phase of HLI recovery after day 14 of HLI; v ) Transcriptome analysis of endothelial cells (ECs) at 14 days post-HLI reveals a disturbed extracellular matrix re-organization in IL-35-injected mice; vi ) IL-35 downregulates three reactive oxygen species (ROS) promoters and upregulates one ROS attenuator, which may functionally mediate IL-35 upregulation of anti-angiogenic extracellular matrix proteins in ECs; and vii ) IL-35 inhibits human microvascular EC migration and tube formation in vitro mainly through upregulating anti-angiogenic extracellular matrix-remodeling proteins. These findings provide a novel insight on the future therapeutic potential of IL-35 in suppressing ischemia/inflammation-triggered inflammatory angiogenesis at early phase but sparing regenerative angiogenesis at late phase.

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Section: Discussionmentioning

confidence: 99%

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Sun

Shao

et al. 2020

Front. Immunol.

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“…Also, intrathecal delivery of IL-35 in an experimental murine model of autoimmune encephalomyelitis (EAE) reduced pain behaviors (i.e., facial allodynia and grimacing), which was noted to occur through an upregulation of an inflammatory cytokine, IL-10 (195). IL-35 has been very recently highlighted as a candidate target for diabetic neuropathic pain (DNP) treatment (78). In fact, in a streptozotocin-induced DNP rat model, other than a protective effect against inflammatory response, IL-35 injected intrathecally reduced allodynia via inhibition of JNK signaling (78).…”

Section: Spinal Cordmentioning

confidence: 99%

“…IL-35 has been very recently highlighted as a candidate target for diabetic neuropathic pain (DNP) treatment (78). In fact, in a streptozotocin-induced DNP rat model, other than a protective effect against inflammatory response, IL-35 injected intrathecally reduced allodynia via inhibition of JNK signaling (78).…”

Section: Spinal Cordmentioning

confidence: 99%

Neuraxial Cytokines in Pain States

et al. 2020

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A high-intensity potentially tissue-injuring stimulus generates a homotopic response to escape the stimulus and is associated with an affective phenotype considered to represent pain. In the face of tissue or nerve injury, the afferent encoding systems display robust changes in the input-output function, leading to an ongoing sensation reported as painful and sensitization of the nociceptors such that an enhanced pain state is reported for a given somatic or visceral stimulus. Our understanding of the mechanisms underlying this non-linear processing of nociceptive stimuli has led to our appreciation of the role played by the functional interactions of neural and immune signaling systems in pain phenotypes. In pathological states, neural systems interact with the immune system through the actions of a variety of soluble mediators, including cytokines. Cytokines are recognized as important mediators of inflammatory and neuropathic pain, supporting system sensitization and the development of a persistent pathologic pain. Cytokines can induce a facilitation of nociceptive processing at all levels of the neuraxis including supraspinal centers where nociceptive input evokes an affective component of the pain state. We review here several key proinflammatory and anti-inflammatory cytokines/chemokines and explore their underlying actions at four levels of neuronal organization: (1) peripheral nociceptor termini; (2) dorsal root ganglia; (3) spinal cord; and (4) supraspinal areas. Thus, current thinking suggests that cytokines by this action throughout the neuraxis play key roles in the induction of pain and the maintenance of the facilitated states of pain behavior generated by tissue injury/inflammation and nerve injury.

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“…Anti-inflammatory cytokine IL-35 was antinociceptive in an autoimmune encephalomyelitis pain model [666]. The anti-inflammatory properties of IL-35 were also shown in a model of diabetic neuropathy, associated with JNK downregulation [667] and neuroprotective microglial M2 polarization [668].…”

Section: Il-27 and Il-35mentioning

confidence: 89%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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IL-35 alleviates inflammation progression in a rat model of diabetic neuropathic pain via inhibition of JNK signaling

Cited by 26 publications

References 29 publications

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Interleukin 35 Delays Hindlimb Ischemia-Induced Angiogenesis Through Regulating ROS-Extracellular Matrix but Spares Later Regenerative Angiogenesis

Neuraxial Cytokines in Pain States

Novel Analgesics with Peripheral Targets

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