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Background: That neuroimmune interaction occurs in chronic pain conditions has been established for over a century, since the discovery of neurogenic inflammation in the periphery. However, the central aspects of neuroimmune interactions have not been fully appreciated until the late 1900s, when a growing interest in how cytokines in the cerebrospinal fluid (CSF) might be relevant in chronic pain conditions emerged. Since then, the field has evolved, and nowadays neuroinflammation is considered to be involved in the pathophysiology of chronic pain. Whether or not pain conditions can be called "neuroinflammatory" is a matter of debate. This review summarizes the results from studies investigating cytokines in the CSF in various pain conditions, and critically discusses neuroimmune aspects of pain conditions using previously proposed hallmarks of neuroinflammation as a framework., Summary: Fifty-two papers were summarized and their results evaluated according to (a) the level of the measured cytokines in patients compared to controls, and (b) the correlation between cytokine level and pain intensity. A subdivision based on pain type was also conducted for each of the 52 studies. A total of 49 proteins have been studied in at least 5 studies, 21 of which were upregulated in a majority of studies. IL-8 was specifically upregulated in a majority of studies of nociceptive pain conditions. Regarding correlation to pain intensity, there is a scarcity of data but 31 proteins were upregulated and correlated with pain in at least one study. Of these, 24 proteins were negatively correlated with pain, and 7 were positively correlated. None of the most studied cytokines, such as TNF, IL-1b, IL-6, IL-8, CCL2/MCP1, BDNF, or bNGF, were consistently correlated to pain., Key Messages: There is sufficient evidence to say that chronic pain conditions come with an upregulation of several cytokines. However, the majority of correlations to symptomatology seem to be negative, indicating that the cytokines might play a protective role that has not been broadly considered. Calling chronic pain conditions neuroinflammatory seems wrong; instead, a more suitable term for depicting the findings would, perhaps, be to talk about neuroimmune activation., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Survivors of acute lymphoblastic leukemia (ALL), the most common childhood cancer, are at increased risk for long-term cognitive problems, including executive function deficits. The chemotherapeutic agent methotrexate (MTX) is used to treat most ALL patients and is closely associated with cognitive deficits. To address how early life cancer chemotherapy leads to cognitive deficits, we developed a translationally relevant mouse model of leukemia survival that exposed mice to leukemic cells and chemotherapeutic drugs (vincristine and MTX, with leucovorin rescue) in early life. Male and female mice were tested several weeks later using novel object recognition (recognition memory) and 5-choice serial reaction time task (executive function). Gene expression of proinflammatory, white matter and synapse-associated molecules was assessed in the prefrontal cortex and small intestine both acutely after chemotherapy and chronically after cognitive testing. Early life cancer-chemotherapy exposure resulted in recognition memory and executive function deficits in adult male mice. Prefrontal cortex expression of the chemokine Ccl2 was increased acutely, while small intestine expression of the proinflammatory cytokine tumor necrosis factor-alpha was elevated both acutely (both sexes) and chronically (males only). Inflammation in the small intestine was correlated with prefrontal cortical proinflammatory and synaptic gene expression changes, as well as to executive function deficits. Collectively, these data indicate that the current protocol results in a robust mouse model in which to study cognitive deficits in leukemia survivors, and suggest that small intestine inflammation may represent a novel contributor to adverse CNS consequences of early life chemotherapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In response to tissue injury or infection, the peripheral tissue macrophage induces an inflammatory response through the release of IL-1beta (interleukin-1beta) and TNFalpha (tumour necrosis factor alpha). These cytokines stimulate macrophages and endothelial cells to express chemokines and adhesion molecules that attract leucocytes into the peripheral site of injury or infection. The aims of the present review are to (i) discuss the relevance of brain (peri)vascular cells and compartments to bacterial meningitis, HIV-1-associated dementia, multiple sclerosis, ischaemic and traumatic brain injury, and Alzheimer's disease, and (ii) to provide an overview of the production and action of pro-inflammatory cytokines by (peri)vascular cells in these pathologies of the CNS (central nervous system). The brain (peri)vascular compartments are highly relevant to pathologies affecting the CNS, as infections are almost exclusively blood-borne. Insults disrupt blood and energy flow to neurons, and active brain-to-blood transport mechanisms, which are the bottleneck in the clearance of unwanted molecules from the brain. Perivascular macrophages are the most reactive cell type and produce IL-1beta and TNFalpha after infection or injury to the CNS. The main cellular target for IL-1beta and TNFalpha produced in the brain (peri)vascular compartment is the endothelium, where these cytokines induce the expression of adhesion molecules and promote leucocyte infiltration. Whether this and other effects of IL-1 and TNF in the brain (peri)vascular compartments are detrimental or beneficial in neuropathology remains to be shown and requires a clear understanding of the role of these cytokines in both damaging and repair processes in the CNS.

Sickness behaviour represents the expression of the adaptive reorganization of the priorities of the host during an infectious episode. This process is triggered by pro-inflammatory cytokines produced by peripheral phagocytic cells in contact with invading micro-organisms. The peripheral immune message is relayed to the brain via a fast neural pathway and a slower humoral pathway, resulting in the expression of pro-inflammatory cytokines in macrophage-like cells and microglia in the brain. The cellular and molecular components of this previously unsuspected system are being progressively identified. These advances are opening new avenues for understanding brain disorders, including depression.