Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice
•IL-35 reduces mechanical pain more prominently in male than female mice with CCI.•CCI induces inflammatory microglial markers in the spinal cord dorsal horn.•IL-35 dampens expression of inflammatory microglial markers in male mice.•IL-35 promotes expression of anti-inflammatory microglial markers i...
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description | •IL-35 reduces mechanical pain more prominently in male than female mice with CCI.•CCI induces inflammatory microglial markers in the spinal cord dorsal horn.•IL-35 dampens expression of inflammatory microglial markers in male mice.•IL-35 promotes expression of anti-inflammatory microglial markers in male mice.•IL-35 alters phenotype, phagocytosis, and cytokines in male microglial cultures.
Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain. |
doi_str_mv | 10.1016/j.bbi.2024.07.043 |
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Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.</description><identifier>ISSN: 0889-1591</identifier><identifier>ISSN: 1090-2139</identifier><identifier>EISSN: 1090-2139</identifier><identifier>DOI: 10.1016/j.bbi.2024.07.043</identifier><identifier>PMID: 39097202</identifier><language>eng</language><publisher>Netherlands: Elsevier Inc</publisher><subject>Interleukin-35 ; Microglia ; Neuroimmune ; Neuropathic pain ; Peripheral nerve injury ; Sex differences</subject><ispartof>Brain, behavior, and immunity, 2024-11, Vol.122, p.287-300</ispartof><rights>2024 The Author(s)</rights><rights>Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c278t-39ee44ed4fa40fbb9427e17d6ca738a2f1c56e5e29763fbbe6857b14ff7d15eb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.bbi.2024.07.043$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39097202$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fiore, Nathan T.</creatorcontrib><creatorcontrib>Hayes, Jessica P.</creatorcontrib><creatorcontrib>Williams, Sarah I.</creatorcontrib><creatorcontrib>Moalem-Taylor, Gila</creatorcontrib><title>Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice</title><title>Brain, behavior, and immunity</title><addtitle>Brain Behav Immun</addtitle><description>•IL-35 reduces mechanical pain more prominently in male than female mice with CCI.•CCI induces inflammatory microglial markers in the spinal cord dorsal horn.•IL-35 dampens expression of inflammatory microglial markers in male mice.•IL-35 promotes expression of anti-inflammatory microglial markers in male mice.•IL-35 alters phenotype, phagocytosis, and cytokines in male microglial cultures.
Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.</description><subject>Interleukin-35</subject><subject>Microglia</subject><subject>Neuroimmune</subject><subject>Neuropathic pain</subject><subject>Peripheral nerve injury</subject><subject>Sex differences</subject><issn>0889-1591</issn><issn>1090-2139</issn><issn>1090-2139</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNp9kEFv1DAQhS0EokvbH8AF5cglwY6TOBYnVNFSqRIXOFuOPaazOE6wnZV646fjaAtHTiPP-97T-BHyltGGUTZ8ODbThE1L266hoqEdf0EOjEpat4zLl-RAx1HWrJfsgrxJ6Ugp7TkbX5MLLqkUxXcgv-9Dhuhh-4mh5n2lvYcT6gypCrDFZdX5EU21agyVDrbCYDdTRL0_M9YYnNfzrPMSn6r0iC4XpEorBu2rGU1cfnjU-y5APEHhj1sEW83aw67DFXnltE9w_Twvyffbz99uvtQPX-_ubz491KYVY665BOg6sJ3THXXTJLtWABN2MFrwUbeOmX6AHlopBl50GMZeTKxzTljWw8Qvyftz7hqXXxukrGZMBrzXAZYtKU5HMciRCVpQdkbL9SlFcGqNOOv4pBhVe_HqqErxai9eUaFK8cXz7jl-m2aw_xx_my7AxzMA5ZMnhKiSQQgGLEYwWdkF_xP_BxtQlh8</recordid><startdate>20241101</startdate><enddate>20241101</enddate><creator>Fiore, Nathan T.</creator><creator>Hayes, Jessica P.</creator><creator>Williams, Sarah I.</creator><creator>Moalem-Taylor, Gila</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>20241101</creationdate><title>Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice</title><author>Fiore, Nathan T. ; Hayes, Jessica P. ; Williams, Sarah I. ; Moalem-Taylor, Gila</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c278t-39ee44ed4fa40fbb9427e17d6ca738a2f1c56e5e29763fbbe6857b14ff7d15eb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Interleukin-35</topic><topic>Microglia</topic><topic>Neuroimmune</topic><topic>Neuropathic pain</topic><topic>Peripheral nerve injury</topic><topic>Sex differences</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Fiore, Nathan T.</creatorcontrib><creatorcontrib>Hayes, Jessica P.</creatorcontrib><creatorcontrib>Williams, Sarah I.</creatorcontrib><creatorcontrib>Moalem-Taylor, Gila</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Brain, behavior, and immunity</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fiore, Nathan T.</au><au>Hayes, Jessica P.</au><au>Williams, Sarah I.</au><au>Moalem-Taylor, Gila</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice</atitle><jtitle>Brain, behavior, and immunity</jtitle><addtitle>Brain Behav Immun</addtitle><date>2024-11-01</date><risdate>2024</risdate><volume>122</volume><spage>287</spage><epage>300</epage><pages>287-300</pages><issn>0889-1591</issn><issn>1090-2139</issn><eissn>1090-2139</eissn><abstract>•IL-35 reduces mechanical pain more prominently in male than female mice with CCI.•CCI induces inflammatory microglial markers in the spinal cord dorsal horn.•IL-35 dampens expression of inflammatory microglial markers in male mice.•IL-35 promotes expression of anti-inflammatory microglial markers in male mice.•IL-35 alters phenotype, phagocytosis, and cytokines in male microglial cultures.
Immune cells are critical in promoting neuroinflammation and neuropathic pain and in facilitating pain resolution, depending on their inflammatory and immunoregulatory cytokine response. Interleukin (IL)-35, secreted by regulatory immune cells, is a member of the IL-12 family with a potent immunosuppressive function. In this study, we investigated the effects of IL-35 on pain behaviors, spinal microglia phenotype following peripheral nerve injury, and in vitro microglial cultures in male and female mice. Intrathecal recombinant IL-35 treatment alleviated mechanical pain hypersensitivity prominently in male mice, with only a modest effect in female mice after sciatic nerve chronic constriction injury (CCI). IL-35 treatment resulted in sex-specific microglial changes following CCI, reducing inflammatory microglial markers and upregulating anti-inflammatory markers in male mice. Spatial transcriptomic analysis revealed that IL-35 suppressed microglial complement activation in the superficial dorsal horn in male mice after CCI. Moreover, in vitro studies showed that IL-35 treatment of cultured inflammatory microglia mitigated their hypertrophied morphology, increased their cell motility, and decreased their phagocytic activity, indicating a phenotypic shift towards homeostatic microglia. Further, IL-35 altered microglial cytokines/chemokines in vitro, suppressing the release of IL-9 and monocyte-chemoattractant protein-1 and increasing IL-10 in the supernatant of male microglial cultures. Our findings indicate that treatment with IL-35 modulates spinal microglia and alleviates neuropathic pain in male mice, suggesting IL-35 as a potential sex-specific targeted immunomodulatory treatment for neuropathic pain.</abstract><cop>Netherlands</cop><pub>Elsevier Inc</pub><pmid>39097202</pmid><doi>10.1016/j.bbi.2024.07.043</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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subjects | Interleukin-35 Microglia Neuroimmune Neuropathic pain Peripheral nerve injury Sex differences |
title | Interleukin-35 alleviates neuropathic pain and induces an anti-inflammatory shift in spinal microglia in nerve-injured male mice |
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