Myostatin and CXCL11 promote nervous tissue macrophages to maintain osteoarthritis pain.

Pain is the most debilitating symptom of knee osteoarthritis (OA) that can even persist after total knee replacement. The severity and duration of pain do not correlate well with joint tissue alterations, suggesting other mechanisms may drive pain persistence in OA. Previous work identified that macrophages accumulate in the dorsal root ganglia (DRG) containing the somas of sensory neurons innervating the injured knee joint in a mouse OA model and acquire a M1-like phenotype to maintain pain.

NLRP3 inflammasome activation in sensory neurons promotes chronic inflammatory and osteoarthritis pain.

Pain is one of the most debilitating symptoms in rheumatic diseases. Pain often persists after total knee replacement in osteoarthritis, or when inflammation is minimal/absent in rheumatoid arthritis. This suggests that pain transitions to a chronic state independent of the original damage/inflammation.

Mitochondria and sensory processing in inflammatory and neuropathic pain.

Rheumatic diseases, such as osteoarthritis and rheumatoid arthritis, affect over 750 million people worldwide and contribute to approximately 40% of chronic pain cases. Inflammation and tissue damage contribute to pain in rheumatic diseases, but pain often persists even when inflammation/damage is resolved. Mechanisms that cause this persistent pain are still unclear.

Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain.

The current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight into how inflammatory pain is resolved is lacking.

The methyltransferase METTL9 mediates pervasive 1-methylhistidine modification in mammalian proteomes.

Post-translational methylation plays a crucial role in regulating and optimizing protein function. Protein histidine methylation, occurring as the two isomers 1- and 3-methylhistidine (1MH and 3MH), was first reported five decades ago, but remains largely unexplored. Here we report that METTL9 is a broad-specificity methyltransferase that mediates the formation of the majority of 1MH present in mouse and human proteomes.

GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity.

Macrophages are key effector cells in obesity-associated inflammation. G protein-coupled receptor kinase 2 (GRK2) is highly expressed in different immune cell types. Using LysM-GRK2 mice, we uncover that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) through modulation of the macrophage pro-inflammatory profile.

Human FAM173A is a mitochondrial lysine-specific methyltransferase that targets adenine nucleotide translocase and affects mitochondrial respiration.

Lysine methylation is a common posttranslational modification of nuclear and cytoplasmic proteins but is also present in mitochondria. The human protein denoted "family with sequence similarity 173 member B" (FAM173B) was recently uncovered as a mitochondrial lysine (K)-specific methyltransferase (KMT) targeting the c-subunit of mitochondrial ATP synthase (ATPSc), and was therefore renamed ATPSc-KMT. We here set out to investigate the biochemical function of its yet uncharacterized paralogue FAM173A.

Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase.

Lysine methylation is an important post-translational modification that is also present on mitochondrial proteins, but the mitochondrial lysine-specific methyltransferases (KMTs) responsible for modification are in most cases unknown. Here, we set out to determine the function of human family with sequence similarity 173 member B (FAM173B), a mitochondrial methyltransferase (MTase) reported to promote chronic pain. Using bioinformatics analyses and biochemical assays, we found that FAM173B contains an atypical, noncleavable mitochondrial targeting sequence responsible for its localization to mitochondria.

Identification of FAM173B as a protein methyltransferase promoting chronic pain.

Chronic pain is a debilitating problem, and insights in the neurobiology of chronic pain are needed for the development of novel pain therapies. A genome-wide association study implicated the 5p15.2 region in chronic widespread pain.

Divergent roles of immune cells and their mediators in pain.

Chronic pain is a major debilitating condition that is difficult to treat. Although chronic pain may appear to be a disorder of the nervous system, crucial roles for immune cells and their mediators have been identified as important contributors in various types of pain. This review focuses on how the immune system regulates pain and discusses the emerging roles of immune cells in the initiation or maintenance of chronic pain.

IL4-10 Fusion Protein Is a Novel Drug to Treat Persistent Inflammatory Pain.

Unlabelled: Chronic pain is a major clinical problem that is difficult to treat and requires novel therapies. Although most pain therapies primarily target neurons, neuroinflammatory processes characterized by spinal cord and dorsal root ganglion production of proinflammatory cytokines play an important role in persistent pain states and represent potential therapeutic targets. Anti-inflammatory cytokines are attractive candidates to regulate aberrant neuroinflammatory processes, but the therapeutic potential of these cytokines as stand-alone drugs is limited.

Reversal of diet-induced obesity and insulin resistance by inducible genetic ablation of GRK2.

Insulin resistance is a common feature of obesity and predisposes individuals to various prevalent pathological conditions. G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2) integrates several signal transduction pathways and is emerging as a physiologically relevant inhibitor of insulin signaling. GRK2 abundance is increased in humans with metabolic syndrome and in different murine models of insulin resistance.

Monocytes/Macrophages control resolution of transient inflammatory pain.

Unlabelled: Insights into mechanisms governing resolution of inflammatory pain are of great importance for many chronic pain-associated diseases. Here we investigate the role of macrophages/monocytes and the anti-inflammatory cytokine interleukin-10 (IL-10) in the resolution of transient inflammatory pain. Depletion of mice from peripheral monocytes/macrophages delayed resolution of intraplantar IL-1β- and carrageenan-induced inflammatory hyperalgesia from 1 to 3 days to >1 week.

A novel p38 MAPK docking-groove-targeted compound is a potent inhibitor of inflammatory hyperalgesia.

The MAPK (mitogen-activated protein kinase) p38 is an important mediator of inflammation and of inflammatory and neuropathic pain. We have described recently that docking-groove-dependent interactions are important for p38 MAPK-mediated signal transduction. Thus virtual screening was performed to identify putative docking-groove-targeted p38 MAPK inhibitors.

Balancing GRK2 and EPAC1 levels prevents and relieves chronic pain.

Chronic pain is a major clinical problem, yet the mechanisms underlying the transition from acute to chronic pain remain poorly understood. In mice, reduced expression of GPCR kinase 2 (GRK2) in nociceptors promotes cAMP signaling to the guanine nucleotide exchange factor EPAC1 and prolongs the PGE2-induced increase in pain sensitivity (hyperalgesia). Here we hypothesized that reduction of GRK2 or increased EPAC1 in dorsal root ganglion (DRG) neurons would promote the transition to chronic pain.

Mesenchymal stem cell transplantation attenuates brain injury after neonatal stroke.

Background And Purpose: Brain injury caused by stroke is a frequent cause of perinatal morbidity and mortality with limited therapeutic options. Mesenchymal stem cells (MSC) have been shown to improve outcome after neonatal hypoxic-ischemic brain injury mainly by secretion of growth factors stimulating repair processes. We investigated whether MSC treatment improves recovery after neonatal stroke and whether MSC overexpressing brain-derived neurotrophic factor (MSC-BDNF) further enhances recovery.

Astrocyte GRK2 as a novel regulator of glutamate transport and brain damage.

G protein-coupled receptor (GPCR) kinase 2 (GRK2) regulates cellular signaling via desensitization of GPCRs and by direct interaction with intracellular signaling molecules. We recently described that ischemic brain injury decreases cerebral GRK2 levels. Here we studied the effect of astrocyte GRK2-deficiency on neonatal brain damage in vivo.

Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region.

Background And Objectives: Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48-52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.

Methods: We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls.

MicroRNA-124 as a novel treatment for persistent hyperalgesia.

Background: Chronic pain is often associated with microglia activation in the spinal cord. We recently showed that microglial levels of the kinase G protein-coupled receptor kinase (GRK)2 are reduced in models of chronic pain. We also found that mice with a cell-specific reduction of around 50% in GRK2 level in microglia/macrophages (LysM-GRK2+/- mice) develop prolonged inflammatory hyperalgesia concomitantly with ongoing spinal microglia/macrophage activation.

G protein-coupled receptor kinase 6 acts as a critical regulator of cytokine-induced hyperalgesia by promoting phosphatidylinositol 3-kinase and inhibiting p38 signaling.

The molecular mechanisms determining magnitude and duration of inflammatory pain are still unclear. We assessed the contribution of G protein-coupled receptor kinase (GRK)-6 to inflammatory hyperalgesia in mice. We showed that GRK6 is a critical regulator of severity and duration of cytokine-induced hyperalgesia.

Glucocorticoid receptor pathway components predict posttraumatic stress disorder symptom development: a prospective study.

Background: Biological correlates of posttraumatic stress disorder (PTSD) have mostly been studied using cross-sectional or posttrauma prospective designs. Therefore, it remains largely unknown whether previously observed biological correlates of PTSD precede trauma exposure. We investigated whether glucocorticoid receptor (GR) pathway components assessed in leukocytes before military deployment represent preexisting vulnerability factors for development of PTSD symptoms.

Microglial GRK2: a novel regulator of transition from acute to chronic pain.

Pain is a hallmark of tissue damage and inflammation promoting tissue protection and thereby contributing to repair. Therefore, transient acute pain is an important feature of the adaptive response to damage. However, in a significant number of cases, pain persists for months to years after the problem that originally caused the pain has resolved.

Pre-existing high glucocorticoid receptor number predicting development of posttraumatic stress symptoms after military deployment.

Objective: The development of posttraumatic stress disorder (PTSD) is influenced by preexisting vulnerability factors. The authors aimed at identifying a preexisting biomarker representing a vulnerability factor for the development of PTSD. To that end, they determined whether the dexamethasone binding capacity of leukocytes, as a measure of glucocorticoid receptor (GR) number, before exposure to trauma was a predictor of development of PTSD symptoms.

Low nociceptor GRK2 prolongs prostaglandin E2 hyperalgesia via biased cAMP signaling to Epac/Rap1, protein kinase Cepsilon, and MEK/ERK.

Hyperexcitability of peripheral nociceptive pathways is often associated with inflammation and is an important mechanism underlying inflammatory pain. Here we describe a completely novel mechanism via which nociceptor G-protein-coupled receptor kinase 2 (GRK2) contributes to regulation of inflammatory hyperalgesia. We show that nociceptor GRK2 is downregulated during inflammation.