A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC. The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group. Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Epidermal hyperinnervation is a critical feature of pruritus during skin inflammation. However, the mechanisms underlying epidermal hyperinnervation are unclear. This study investigates the role of the transcription factor EGR1 in epidermal innervation by utilizing wild-type (Egr1+/+) and Egr1-null (Egr1‒/‒) mice topically applied Dermatophagoides farinae extract from dust mite. Our findings revealed that Egr1‒/‒ mice exhibited reduced scratching behaviors and decreased density of epidermal innervation compared with Egr1+/+ mice. Furthermore, we identified artemin, a neurotrophic factor, as an EGR1 target responsible for Dermatophagoides farinae extract-induced hyperinnervation. It has been demonstrated that Dermatophagoides farinae extract stimulates toll-like receptors in keratinocytes. To elucidate the cellular mechanism, we stimulated keratinocytes with Pam3CSK4, a toll-like receptor 1/2 ligand. Pam3CSK4 triggered a toll-like receptor 1/2-mediated signaling cascade involving IRAK4, IκB kinase, MAPKs, ELK1, EGR1, and artemin, leading to increased neurite outgrowth and neuronal migration. In addition, increased expression of EGR1 and artemin was observed in the skin tissues of patients with atopic dermatitis. These findings highlight the significance of the EGR1-artemin axis in keratinocytes, promoting the process of epidermal innervation and suggesting it as a potential therapeutic target for alleviating itch and pain associated with house dust mite-induced skin inflammation.

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There have been significant developments in understanding artemin/GFRα3 signaling in recent years, and there is now accumulating evidence that artemin has important roles to play in pain signaling, including that derived from joint and bone, and that associated with osteorthritis (OA).
A total of 163 Sprague-Dawley rats were used in this study. We used an animal model of mono-iodoacetate (MIA)-induced OA, in combination with electrophysiology, behavioral testing, Western blot analysis, and retrograde tracing and immunohistochemistry, to identify roles for artemin/GFRα3 signaling in the pathogenesis of OA pain.
We have found that: 1) GFRα3 is expressed in a substantial proportion of knee joint afferent neurons; 2) exogenous artemin sensitizes knee joint afferent neurons in naïve rats; 3) artemin is expressed in articular tissues of the joint, but not surrounding bone, early in MIA-induced OA; 4) artemin expression increases in bone later in MIA-induced OA when pathology involves subchondral bone; and 5) sequestration of artemin reverses MIA-induced sensitization of both knee joint and bone afferent neurons late in disease when there is inflammation of knee joint tissues and damage to the subchondral bone.
Our findings show that artemin/GFRα3 signaling has a role to play in the pathogenesis of OA pain, through effects on both knee joint and bone afferent neurons, and suggest that targeted manipulation of artemin/GFRα3 signaling may provide therapeutic benefit for the management of OA pain.
Data are available on request of the corresponding author.

The protein artemin acts as both an RNA and protein chaperone and constitutes over 10% of all protein in Artemia cysts during diapause. However, its mechanistic details remain elusive since no high-resolution structure of artemin exists. Here we report the full-length structure of artemin at 2.04 Å resolution. The cryo-EM map contains density for an intramolecular disulfide bond between Cys22-Cys61 and resolves the entire C-terminus extending into the core of the assembled protein cage but in a different configuration than previously hypothesized with molecular modeling. We also provide data supporting the role of C-terminal helix F towards stabilizing the dimer form that is believed to be important for its chaperoning activity. We were able to destabilize this effect by placing a tag at the C-terminus to fully pack the internal cavity and cause limited steric hindrance.

The main aim of the study is to analyze the impact of Artemin on survival and prognosis in endometrial cancer (EC) patients by bioinformatics methods. As a member of the glial-derived neurotrophic factor (GDNF) family, Artemin is not only important in the repair process of nerve damage, but also involved in tumorigenesis and metastasis. In this study, we demonstrated that Artemin mRNA was overexpressed in EC tissues. Artemin expression was closely related to the FIGO stage, pathologic differentiation, deep myometrial infiltration, lymphatic metastasis, and survival status. Univariate and multivariate Cox regression analysis showed that ectopic overexpression of Artemin predicted poor survival prognosis. Artemin expression could be used as an independent risk factor for the prognosis of EC patients. The proliferation of EC cells was significantly downregulated by silencing of Artemin. Artemin promotes tumor progression by regulating the proliferation of EC cells, thereby affecting the prognosis of EC patients.

Prolonged social stress is a major cause for depression in humans and is associated with a wide range of subsequent pathophysiological changes such as elevated blood pressure. A routinely used model for investigating this kind of stress in mice is the chronic social defeat paradigm where a smaller intruder is exposed to an aggressive inhabitant of a home cage. This model is restricted to males and includes a high proportion of physical stress that might e.g., interfere with immunological aspects of the stress. The prevalence of depression in humans is even higher in women than in men. Therefore, expanding models to female individuals is desirable. We here tested the social instability model as a tool for administering chronic social stress to female C57BL/6J mice and analyzed short-term as well as long-lasting effects. Animals were housed in groups of four and were shuffled two times a week, resulting in a permanent re-structuration of their social hierarchy. While directly after the stress exposure, serum corticosterone was elevated, increased body weight and fat deposits were observed in stressed mice even one year after discontinuation of the stress. At the behavioral level, animals could be stratified into resilient and susceptible animals directly post-stress, but those subgroups were not distinguishable any more in the long-term analysis. To identify molecular contributors to resilience in the here presented social instability induced stress model, Arc-activity dependent trapping of neurons was conducted in Arc-creERT2/sun1sfGFP mice. RNA samples derived from activated nuclei from the ventral hippocampus, a brain region involved in stress-regulation during attacks or explorative behavior of mice, were subjected to a neurogenesis pathway array. While several genes were differentially regulated by stress, in particular, artemin, a neurotrophic factor was upregulated in resilient versus susceptible individuals.

Osteoarthritis (OA) associated pain (OA-pain) is a significant global problem. OA-pain limits limb use and mobility and is associated with widespread sensitivity. Therapeutic options are limited, and the available options are often associated with adverse effects. The lack of therapeutic options is partly due to a lack of understanding of clinically relevant underlying neural mechanisms of OA-pain. In previous work in naturally occurring OA-pain in dogs, we identified potential signaling molecules (artemin/GFRα3) that were upregulated. Here, we use multiple approaches, including cellular, mouse genetic, immunological suppression in a mouse model of OA, and clinically relevant measures of sensitivity and limb use to explore the functional role of artemin/GFRα3 signaling in OA-pain. We found the monoiodoacetate (MIA)-induced OA-pain in mice is associated with decreased limb use and hypersensitivity. Exogenous artemin induces mechanical, heat, and cold hypersensitivity, and systemic intraperitoneal anti-artemin monoclonal antibody administration reverses this hypersensitivity and restores limb use in mice with MIA-induced OA-pain. An artemin receptor GFRα3 expression is increased in sensory neurons in the MIA model. Our results provide a molecular basis of arthritis pain linked with artemin/GFRα3 signaling and indicate that further work is warranted to investigate the neuronal plasticity and the pathways that drive pain in OA.

ARTEMIN (ARTN), one of the glial-cell derived neurotrophic factor family of ligands, has been reported to be associated with a number of human malignancies. In this study, the enhanced expression of ARTN in colorectal carcinoma (CRC) was observed; the expression of ARTN positively correlated with lymph node metastases and advanced tumor stages and predicted poor prognosis. Forced expression of ARTN in CRC cells enhanced oncogenic behavior, mesenchymal phenotype, stem cell-like properties and tumor growth and metastasis in a xenograft model. These functions were conversely inhibited by depletion of endogenous ARTN. Forced expression of ARTN reduced the sensitivity of CRC cells to 5-FU treatment; and 5-FU resistant CRC cells harbored enhanced expression of ARTN. The oncogenic functions of ARTN were demonstrated to be mediated by p44/42 MAP kinase dependent expression of CDH2 (CADHERIN 2, also known as N-CADHERIN). Inhibition of p44/42 MAP kinase activity or siRNA mediated depletion of endogenous CDH2 reduced the enhanced oncogenicity and chemoresistance consequent to forced expression of ARTN induced cell functions; and forced expression of CDH2 rescued the reduced mesenchymal properties and resistance to 5-FU after ARTN depletion. In conclusion, ARTN may be of prognostic and theranostic utility in CRC.

Benign prostatic hyperplasia/lower urinary tract dysfunction (LUTD) affects nearly all men. Symptoms typically present in the fifth or sixth decade and progressively worsen over the remainder of life. Here, we identify a surprising origin of this disease that traces back to the intrauterine environment of the developing male, challenging paradigms about when this disease process begins. We delivered a single dose of a widespread environmental contaminant present in the serum of most Americans [2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), 1 µg/kg], and representative of a broader class of environmental contaminants, to pregnant mice and observed an increase in the abundance of a neurotrophic factor, artemin, in the developing mouse prostate. Artemin is required for noradrenergic axon recruitment across multiple tissues, and TCDD rapidly increases prostatic noradrenergic axon density in the male fetus. The hyperinnervation persists into adulthood, when it is coupled to autonomic hyperactivity of prostatic smooth muscle and abnormal urinary function, including increased urinary frequency. We offer new evidence that prostate neuroanatomical development is malleable and that intrauterine chemical exposures can permanently reprogram prostate neuromuscular function to cause male LUTD in adulthood.