Neuroblastoma is a type of cancer that most often affects children. Neuroblastoma occurs when immature nerve cells called neuroblasts become abnormal and multiply uncontrollably to form a tumor. Most commonly, the tumor originates in the nerve tissue of the adrenal gland located above each kidney. Other common sites for tumors to form include the nerve tissue in the abdomen, chest, neck, or pelvis. Neuroblastoma can spread (metastasize) to other parts of the body such as the bones, liver, or skin.

Neuroblastoma

The skin is a complex organ that has devised numerous strategies, such as physical, chemical, and microbiological barriers, to protect the host from external insults. In addition, the skin contains an intricate network of immune cells resident to the tissue, crucial for host defense as well as tissue homeostasis. In the event of an insult, the skin-resident immune cells are crucial not only for prevention of infection but also for tissue reconstruction. Deregulation of immune responses often leads to impaired healing and poor tissue restoration and function. In this review, we will discuss the defensive components of the skin and focus on the function of skin-resident immune cells in homeostasis and their role in wound healing.

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The Dynamics of the Skin's Immune System

Inflammation is the body's response to injury and infection, involving a complex biological response of the somatosensory, immune, autonomic, and vascular systems. Inflammatory mediators such as prostaglandin, proinflammatory cytokines, and chemokines induce pain via direct activation of nociceptors, the primary sensory neurons that detect noxious stimuli. Neurogenic inflammation is triggered by nerve activation and results in neuropeptide release and rapid plasma extravasation and edema, contributing to pain conditions such as headache. Neuroinflammation is a localized inflammation in the peripheral nervous system (PNS) and central nervous system (CNS). A characteristic feature of neuroinflammation is the activation of glial cells in dorsal root ganglia, spinal cord, and brain which leads to the production of proinflammatory cytokines and chemokines in the PNS and CNS that drives peripheral sensitization and central sensitization. Here, we discuss the distinct roles of inflammation, neurogenic inflammation, and neuroinflammation in the regulation of different types of pain conditions, with a special focus on neuroinflammation in postoperative pain and opioid-induced hyperalgesia.

Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain.

Pain is a hallmark of tissue injury, inflammatory diseases, pathogen invasion and neuropathy. It is mediated by nociceptor sensory neurons that innervate the skin, joints, bones, muscles and mucosal tissues and protects organisms from noxious stimuli. Nociceptors are sensitized by inflammatory mediators produced by the immune system, including cytokines, lipid mediators and growth factors, and can also directly detect pathogens and their secreted products to produce pain during infection. Upon activation, nociceptors release neuropeptides from their terminals that potently shape the function of innate and adaptive immune cells. For some pathogens, neuron–immune interactions enhance host protection from infection, but for other pathogens, neuron–immune signalling pathways can be exploited to facilitate pathogen survival. Here, we discuss the role of nociceptor interactions with the immune system in pain and infection and how understanding these pathways could produce new approaches to treat infectious diseases and chronic pain. This Review considers the link between pain and the immune system. Nociceptors are directly activated by immune mediators and microbial products and, in turn, release neuropeptides that shape immune responses. These neuroimmune pathways can contribute to protective immunity from infections but also lead to chronic pain.

Pain and immunity: implications for host defence

Pain is the major symptom of osteoarthritis (OA) and is an important factor in strategies to manage this disease. However, the current standard of care does not provide satisfactory pain relief for many patients. The pathophysiology of OA is complex, and its presentation as a clinical syndrome is associated with pathologies of multiple joint tissues. Inflammation is associated with both OA pain and disease outcome and is therefore a major treatment target for OA and OA pain. Unlike TNF inhibitors and IL-1 inhibitors, established drugs such as glucocorticoids and methotrexate can reduce OA pain. Although central nociceptive pathways contribute to OA pain, crosstalk between the immune system and nociceptive neurons is central to inflammatory pain; therefore, new therapies might target this crosstalk. Newly identified drug targets, including neurotrophins and the granulocyte–macrophage colony-stimulating factor (GM-CSF)–CC-chemokine ligand 17 (CCL17) chemokine axis, offer the hope of better results but require clinical validation. Pain management is presently the focus of osteoarthritis (OA) therapy, but traditional pain-relieving drugs such as NSAIDs and glucocorticoids have limited utility. In this Review, the next generation of OA analgesics and their potential mechanisms of action are discussed.

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Therapeutic options for targeting inflammatory osteoarthritis pain.

Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection

Neuroblastoma is the second most common tumor in children The cause of neuroblastoma is thought to lie in aberrant development of embryonic neural crest cells and is accompanied by low MHC-1 expression and suppression of the NF-κB transcription factor, thereby gearing cells towards escape from immunosurveillance Here we assess regulation of the MHC-1 gene in neuroblastoma to enhance its immunogenic potential for therapeutic T-cell targeting A genome-wide CRISPR screen identified N4BP1 and TNIP1 as inhibitory factors of NF-κB-mediated MHC-1 expression in neuroblastoma Advanced stage neuroblastoma patients who expressed high levels of TNIP1 and N4BP1 exhibited worse overall survival Depletion of N4BP1 or TNIP1 increased NF-κB and MHC-1 expression and stimulated recognition by antigen-specific CD8+ T cells We confirmed that TNIP1 inhibited canonical NF-κB member RelA by preventing activation of the RelA/p50 NF-κB dimer Furthermore, N4BP1 inhibited both canonical and non-canonical NF-κB through binding of deubiquitinating enzyme CEZANNE, resulting in stabilization of TRAF3 and degradation of NF-κB-inducing kinase NIK These data suggest N4BP1/CEZANNE or TNIP1 may be candidate targets for immunotherapy in neuroblastoma tumors and should lift NF-κB suppression, thereby triggering increased peptide/MHC1-mediated tumor reactivity to enhance therapeutic T cell targeting

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Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma.

Post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) is an important element of the management of patients with residual tumour after chemotherapy for disseminated nonseminomatous germ cell tumour (NSGCT). This is a challenging procedure and the outcome varies widely between institutions. There is much debate concerning the anatomical extent of the dissection and the literature is conflicting regarding the outcome of this procedure. In this systematic review we aim to summarise the literature on the relapse rate of PC-RPLND. We performed a search of the literature of the PubMed/MEDLINE and Embase databases, in accordance with the PRISMA guidelines. Studies reporting on the relapse rate of PC-RPLND in NSGCT patients with residual tumour were eligible for inclusion. We calculated the weighted average relapse rates of included studies and assessed the risk of bias using the Newcastle-Ottawa scale. A total of 33 studies, reporting on 2,379 patients undergoing open PC-RPLND (O-RPLND) and 463 patients undergoing minimally invasive PC-RPLND (MI-RPLND) were included. The weighted average relapse rates were 11.4% for O-RPLND, and 3.0% for MI-RPLND. The rates of retroperitoneal relapse were 4.6% and 1.7% after O-RPLND and MI-RPLND, respectively. For O-RPLND specifically, the average retroperitoneal relapse rate was 3.1% after modified dissection and 6.1% after bilateral dissection. We conclude that modified template dissection is oncologically safe in carefully selected patients. Minimally invasive procedures are feasible but long-term data on the oncological outcome are still lacking. PC-RPLND is a complex and challenging procedure, and patients should be treated at high-volume expert centres.

Rianne Haarsma

Papers

Blocking Neuronal Signaling to Immune Cells Treats Streptococcal Invasive Infection

Nedd4-Binding Protein 1 and TNFAIP3-Interacting Protein 1 Control MHC-1 Display in Neuroblastoma.

Clinical outcome of post-chemotherapy retroperitoneal lymph node dissection in metastatic nonseminomatous germ cell tumour: A systematic review.

Added value of repeat sentinel lymph node biopsy in FDG-PET/CT node-negative patients with ipsilateral breast cancer recurrence