Biology subjects

Folger, J. K.

Publications and source records attributed to Folger, J. K..

4 recordsLinked to original sources

bioRxiv2024

Mast cell-derived chymases are essential for the resolution of inflammatory pain in mice

Immune cells play a critical role in the transition from acute to chronic pain. However, the role of mast cells in pain remains under-investigated. Here, we demonstrated that the resolution of inflammatory pain is markedly delayed in mast-cell-deficient mice. In response to Complete Freund Adjuvant (CFA), mast-cell-deficient mice showed greater levels of nitric oxide and altered cytokine/chemokine profile in inflamed skin in both sexes. In Wild-Type (WT) mice, the number of mast cell and mast cell-derived chymases; chymase 1 (CMA1) and mast cell protease 4 (MCPT4) increased in the inflamed skin. Inhibiting chymase enzymatic activity delayed the resolution of inflammatory pain. Consistently, local pharmacological administration of recombinant CMA1 and MCPT4 promoted the resolution of pain hypersensitivity and attenuated the upregulation of cytokines and chemokines under inflammation. We identified CCL9 as a target of MCPT4. Inhibition of CCL9 promoted recruitment of CD206+ myeloid cells and alleviated inflammatory pain. Our work reveals a new role of mast cell-derived chymases in preventing the transition from acute to chronic pain and suggests new therapeutic avenues for the treatment of inflammatory pain. SummaryMast cell-derived chymases play an unexpected role in the resolution of inflammatory pain and regulate the immune response. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/606617v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@ba757dorg.highwire.dtl.DTLVardef@17783c4org.highwire.dtl.DTLVardef@16be9d3org.highwire.dtl.DTLVardef@1c42bc2_HPS_FORMAT_FIGEXP M_FIG Mast cells derived chymase MCPT4 degrades CCL9 to promote acute inflammatory pain resolution and prevent chronic pain. CFA-induced inflammation increases mast cells that degranulate and release chymases, like MCPT4 and CMA1, which in turn cleaves cytokines and chemokines such as CCL9. CCL9 cleavage induces the recruitment of CD206+ myeloid cells to promote the resolution of pain and prevent the transition from acute to chronic pain. C_FIG

immunology↗

bioRxiv2023

Interleukin-10-producing monocytes contribute to sex differences in pain resolution in mice and humans.

Pain is closely associated with the immune system, which exhibits sexual dimorphism. For these reasons, neuro-immune interactions are suggested to drive sex differences in pain pathophysiology. However, our understanding of peripheral neuro-immune interactions on sex differences in pain resolution remains limited. Here, we have shown, in both a mouse model of inflammatory pain and in humans following traumatic pain, that males had higher levels of interleukin (IL)-10 than females, which were correlated with faster pain resolution. Following injury, we identified monocytes (CD11b+ Ly6C+ Ly6G-F4/80mid) as the primary source of IL-10, with IL-10-producing monocytes being more abundant in males than females. In a mouse model, neutralizing IL-10 signaling through antibodies, genetically ablating IL-10R1 in sensory neurons, or depleting monocytes with clodronate all impaired the resolution of pain hypersensitivity in both sexes. Furthermore, manipulating androgen levels in mice reversed the sexual dimorphism of pain resolution and the levels of IL-10-producing monocytes. These results highlight a novel role for androgen-driven peripheral IL-10-producing monocytes in the sexual dimorphism of pain resolution. These findings add to the growing concept that immune cells play a critical role in resolving pain and preventing the transition into chronic pain. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/565129v1_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@6e158corg.highwire.dtl.DTLVardef@148c8b5org.highwire.dtl.DTLVardef@1711d2dorg.highwire.dtl.DTLVardef@132a755_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Tonic Meningeal Interleukin-10 Upregulates Delta Opioid Receptor to Prevent Relapse to Pain

Chronic pain often alternates between transient remission and relapse of severe pain. While most research on chronic pain has focused on mechanisms maintaining pain, there is a critical unmet need to understand what prevents pain from re-emerging in those who recover from acute pain. We found that interleukin (IL)-10, a pain resolving cytokine, is persistently produced by resident macrophages in the spinal meninges during remission from pain. IL-10 upregulated expression and analgesic activity of {delta}-opioid receptor ({delta}OR) in the dorsal root ganglion. Genetic or pharmacological inhibition of IL-10 signaling or {delta}OR triggered relapse to pain in both sexes. These data challenge the widespread assumption that remission of pain is simply a return to the naive state before pain was induced. Instead, our findings strongly suggest a novel concept that: remission is a state of lasting pain vulnerability that results from a long-lasting neuroimmune interactions in the nociceptive system.

neuroscience↗

bioRxiv2022

Head and Neck Cancer-derived small extracellular vesicles sensitize TRPV1+ neurons to mediate cancer pain

Severe pain is often experienced by patients with head and neck cancer and is associated with a poor prognosis. Despite its frequency and severity, current treatments fail to adequately control cancer-associated pain, because of our lack of mechanistic understanding. Cancer-derived small extracellular vesicles (Cancer-sEVs) are well- positioned to function as mediators of communication between cancer cells and neurons. Inhibition of Cancer-sEV release attenuated pain in tumor-bearing mice. Injection of purified Cancer-sEVs is sufficient to induce pain hypersensitivity in naive mice. Cancer-sEVs triggered calcium influx in nociceptors and inhibition or ablation of nociceptors protect against cancer pain. Interrogation of published sequencing data of human sensory neurons exposed to human Cancer-sEVs suggested a stimulation of protein translation in neurons. Induction of translation by Cancer-sEVs was validated in our mouse model and its inhibition alleviated cancer pain in mice. These findings define a role of Cancer-sEVs in cancer pain and identify several druggable targets. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=135 SRC="FIGDIR/small/506411v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@2a13a2org.highwire.dtl.DTLVardef@6f305dorg.highwire.dtl.DTLVardef@1d0417corg.highwire.dtl.DTLVardef@17b36df_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗