Journal of Neurochemistry

doi: 10.1111/jnc.15862pmid: N/A

Godbout, Jonathan

doi: 10.1111/jnc.16192pmid: 39092667

This preface introduces the Special Issue on Neuroimmunology in the Journal of Neurochemistry. The basis of neuroimmunology is to understand functional interactions between cells of the immune system and the central nervous system (CNS). These cells communicate across systems because they share signaling molecules and corresponding receptors. Moreover, this cell signaling allows for dynamic bidirectional communication between the immune system and the brain both within the CNS proper as well as across peripheral organs. Because of this, Neuroimmunology intersects with many biological processes including immunity, behavior, endocrinology, metabolism, and pathology. Understanding neuroimmune interactions that influence CNS homeostasis is especially relevant in health and disease. This special issue comprises of 14 articles, representing 9 review articles and 5 original articles, covering the roles of neuroimmunology relevant to CNS injury, CNS & peripheral infections, cancer, Alzheimer's disease, and COVID‐19. Thus, these articles highlight different aspects of neuroimmunology and signaling, and represent progress in understanding the consequences of inflammation on key communication pathways between the immune system and the brains.

Carrillo, Gabriela L.; Su, Jianmin; Cawley, Mikel L.; Wei, Derek; Gill, Simran K.; Blader, Ira J.; Fox, Michael A.

doi: 10.1111/jnc.15770pmid: 36683435

The apicomplexan parasite Toxoplasma gondii has developed mechanisms to establish a central nervous system infection in virtually all warm‐blooded animals. Acute T. gondii infection can cause neuroinflammation, encephalitis, and seizures. Meanwhile, studies in humans, nonhuman primates, and rodents have linked chronic T. gondii infection with altered behavior and increased risk for neuropsychiatric disorders, including schizophrenia. These observations and associations raise questions about how this parasitic infection may alter neural circuits. We previously demonstrated that T. gondii infection triggers the loss of inhibitory perisomatic synapses, a type of synapse whose dysfunction or loss has been linked to neurological and neuropsychiatric disorders. We showed that phagocytic cells (including microglia and infiltrating monocytes) contribute to the loss of these inhibitory synapses. Here, we show that these phagocytic cells specifically ensheath excitatory pyramidal neurons, leading to the preferential loss of perisomatic synapses on these neurons and not those on cortical interneurons. Moreover, we show that infection induces an increased expression of the complement C3 gene, including by populations of these excitatory neurons. Infecting C3‐deficient mice with T. gondii revealed that C3 is required for the loss of perisomatic inhibitory synapses. Interestingly, loss of C1q did not prevent the loss of perisomatic synapses following infection. Together, these findings provide evidence that T. gondii induces changes in excitatory pyramidal neurons that trigger the selective removal of inhibitory perisomatic synapses and provide a role for a nonclassical complement pathway in the remodeling of inhibitory circuits in the infected brain.

Koss, K. M.; Son, T.; Li, C.; Hao, Y.; Cao, J.; Churchward, M. A.; Zhang, Z. J.; Wertheim, J. A.; Derda, R.; Todd, K. G.

doi: 10.1111/jnc.15840pmid: 37171455

Microglia are immune‐derived cells critical to the development and healthy function of the brain and spinal cord, yet are implicated in the active pathology of many neuropsychiatric disorders. A range of functional phenotypes associated with the healthy brain or disease states has been suggested from in vivo work and were modeled in vitro as surveying, reactive, and primed sub‐types of primary rat microglia and mixed microglia/astrocytes. It was hypothesized that the biomolecular profile of these cells undergoes a phenotypical change as well, and these functional phenotypes were explored for potential novel peptide binders using a custom 7 amino acid‐presenting M13 phage library (SX7) to identify unique peptides that bind differentially to these respective cell types. Surveying glia were untreated, reactive were induced with a lipopolysaccharide treatment, recovery was modeled with a potent anti‐inflammatory treatment dexamethasone, and priming was determined by subsequently challenging the cells with interferon gamma. Microglial function was profiled by determining the secretion of cytokines and nitric oxide, and expression of inducible nitric oxide synthase. After incubation with the SX7 phage library, populations of SX7‐positive microglia and/or astrocytes were collected using fluorescence‐activated cell sorting, SX7 phage was amplified in Escherichia coli culture, and phage DNA was sequenced via next‐generation sequencing. Binding validation was done with synthesized peptides via in‐cell westerns. Fifty‐eight unique peptides were discovered, and their potential functions were assessed using a basic local alignment search tool. Peptides potentially originated from proteins ranging in function from a variety of supportive glial roles, including synapse support and pruning, to inflammatory incitement including cytokine and interleukin activation, and potential regulation in neurodegenerative and neuropsychiatric disorders.

Furman, Susana; Green, Kim; Lane, Thomas E.

doi: 10.1111/jnc.15985pmid: 37850241

Coronavirus disease 2019 (COVID‐19) has rapidly escalated into a global pandemic that primarily affects older and immunocompromised individuals due to underlying clinical conditions and suppressed immune responses. Furthermore, COVID‐19 patients exhibit a spectrum of neurological symptoms, indicating that COVID‐19 can affect the brain in a variety of manners. Many studies, past and recent, suggest a connection between viral infections and an increased risk of neurodegeneration, raising concerns about the neurological effects of COVID‐19 and the possibility that it may contribute to Alzheimer's disease (AD) onset or worsen already existing AD pathology through inflammatory processes given that both COVID‐19 and AD share pathological features and risk factors. This leads us to question whether COVID‐19 is a risk factor for AD and how these two conditions might influence each other. Considering the extensive reach of the COVID‐19 pandemic and the devastating impact of the ongoing AD pandemic, their combined effects could have significant public health consequences worldwide.

Mehta, Suresh L.; Arruri, Vijay; Vemuganti, Raghu

doi: 10.1111/jnc.16055pmid: 38279529

Post‐stroke neuroinflammation is pivotal in brain repair, yet persistent inflammation can aggravate ischemic brain damage and hamper recovery. Following stroke, specific molecules released from brain cells attract and activate central and peripheral immune cells. These immune cells subsequently release diverse inflammatory molecules within the ischemic brain, initiating a sequence of events, including activation of transcription factors in different brain cell types that modulate gene expression and influence outcomes; the interactive action of various noncoding RNAs (ncRNAs) to regulate multiple biological processes including inflammation, epitranscriptomic RNA modification that controls RNA processing, stability, and translation; and epigenetic changes including DNA methylation, hydroxymethylation, and histone modifications crucial in managing the genic response to stroke. Interactions among these events further affect post‐stroke inflammation and shape the depth of ischemic brain damage and functional outcomes. We highlighted these aspects of neuroinflammation in this review and postulate that deciphering these mechanisms is pivotal for identifying therapeutic targets to alleviate post‐stroke dysfunction and enhance recovery.

Groh, Adam M. R.; Caporicci‐Dinucci, Nina; Afanasiev, Elia; Bigotte, Maxime; Lu, Brianna; Gertsvolf, Joshua; Smith, Matthew D.; Garton, Thomas; Callahan‐Martin, Liam; Allot, Alexis; Hatrock, Dale J.; Mamane, Victoria; Drake, Sienna; Tai, Huilin; Ding, Jun; Fournier, Alyson E.; Larochelle, Catherine; Calabresi, Peter A.; Stratton, Jo Anne

Braatz, Charlotte; Komes, Max P.; Ravichandran, Kishore Aravind; Fragas, Matheus Garcia; Griep, Angelika; Schwartz, Stephanie; McManus, Róisín M.; Heneka, Michael T.

doi: 10.1111/jnc.15778pmid: 36799439

Alzheimer's disease (AD) is associated with the cerebral deposition of Amyloid‐β (Aβ) peptide, which leads to NLRP3 inflammasome activation and subsequent release of interleukin‐1β (IL‐1β) and interleukin‐18 (IL‐18). NLRP3 reduction has been found to increase microglial clearance, protect from synapse loss, and suppress both the changes to synaptic plasticity and spatial memory dysfunction observed in murine AD models. Here, we test whether NLRP3‐directed antisense oligonucleotides (ASOs) can be harnessed as immune modulators in primary murine microglia and human THP‐1 cells. NLRP3 mRNA degradation was achieved at 72 h of ASO treatment in primary murine microglia. Consequently, NLRP3‐directed ASOs significantly reduced the levels of cleaved caspase‐1 and mature IL‐1β when microglia were either activated by LPS and nigericin or LPS and Aβ. In human THP‐1 cells NLRP3‐targeted ASOs also significantly reduced the LPS plus nigericin‐ or LPS plus Aβ‐induced release of mature IL‐1β. Together, NLRP3‐directed ASOs can suppress NLRP3 inflammasome activity and subsequent release of IL‐1β in primary murine microglia and THP‐1 cells. ASOs may represent a new and alternative approach to modulate NLRP3 inflammasome activation in neurodegenerative diseases, in addition to attempts to inhibit the complex pharmacologically.

Otto‐Dobos, L. D.; Santos, J. C.; Strehle, L. D.; Grant, C. V.; Simon, L. A.; Oliver, B.; Godbout, J. P.; Sheridan, J. F.; Barrientos, R. M.; Glasper, E. R.; Pyter, L. M.

doi: 10.1111/jnc.15830pmid: 37084026

It is poorly understood how solid peripheral tumors affect brain neuroimmune responses despite the various brain‐mediated side effects and higher rates of infection reported in cancer patients. We hypothesized that chronic low‐grade peripheral tumor‐induced inflammation conditions microglia to drive suppression of neuroinflammatory responses to a subsequent peripheral immune challenge. Here, Balb/c murine mammary tumors attenuated the microglial inflammatory gene expression responses to lipopolysaccharide (LPS) and live Escherichia coli (E. coli) challenges and the fatigue response to an E. coli infection. In contrast, the inflammatory gene expression in response to LPS or a toll‐like receptor 2 agonist of Percoll‐enriched primary microglia cultures was comparable between tumor‐bearing and ‐free mice, as were the neuroinflammatory and sickness behavioral responses to an intracerebroventricular interleukin (IL)‐1β injection. These data led to the hypothesis that Balb/c mammary tumors blunt the neuroinflammatory responses to an immune challenge via a mechanism involving tumor suppression of the peripheral humoral response. Balb/c mammary tumors modestly attenuated select circulating cytokine responses to LPS and E. coli challenges. Further, a second mammary tumor/mouse strain model (E0771 tumors in C57Bl/6 mice) displayed mildly elevated inflammatory responses to an immune challenge. Taken together, these data indicate that tumor‐induced suppression of neuroinflammation and sickness behaviors may be driven by a blunted microglial phenotype, partly because of an attenuated peripheral signal to the brain, which may contribute to infection responses and behavioral side effects reported in cancer patients. Finally, these neuroimmune effects likely vary based on tumor type and/or host immune phenotype.

Volk, Parker; Rahmani Manesh, Mohammadreza; Warren, Mary E.; Besko, Katie; Gonçalves de Andrade, Elisa; Wicki‐Stordeur, Leigh E.; Swayne, Leigh Anne

doi: 10.1111/jnc.16016pmid: 38014645

As the COVID‐19 pandemic persists, SARS‐CoV‐2 infection is increasingly associated with long‐term neurological side effects including cognitive impairment, fatigue, depression, and anxiety, colloquially known as “long‐COVID.” While the full extent of long‐COVID neuropathology across years or even decades is not yet known, we can perhaps take direction from long‐standing research into other respiratory diseases, such as influenza, that can present with similar long‐term neurological consequences. In this review, we highlight commonalities in the neurological impacts of influenza and COVID‐19. We first focus on the common potential mechanisms underlying neurological sequelae of long‐COVID and influenza, namely (1) viral neurotropism and (2) dysregulated peripheral inflammation. The latter, namely heightened peripheral inflammation leading to central nervous system dysfunction, is emerging as a shared mechanism in various peripheral inflammatory or inflammation‐associated diseases and conditions. We then discuss historical and modern examples of influenza‐ and COVID‐19‐associated cognitive impairment, depression, anxiety, and fatigue, revealing key similarities in their neurological sequelae. Although we are learning that the effects of influenza and COVID differ somewhat in terms of their influence on the brain, as the impacts of long‐COVID grow, such comparisons will likely prove valuable in guiding ongoing research into long‐COVID, and perhaps foreshadow what could be in store for individuals with COVID‐19 and their brain health.