A body-brain circuit that regulates body inflammatory responses.
Nature
The body-brain axis is emerging as a principal conductor of organismal physiology. It senses and controls organ function, metabolism and nutritional state. Here we show that a peripheral immune insult strongly activates the body-brain axis to regulate immune responses. We demonstrate that pro-inflammatory and anti-inflammatory cytokines communicate with distinct populations of vagal neurons to inform the brain of an emerging inflammatory response. In turn, the brain tightly modulates the course of the peripheral immune response. Genetic silencing of this body-brain circuit produced unregulated and out-of-control inflammatory responses. By contrast, activating, rather than silencing, this circuit affords neural control of immune responses. We used single-cell RNA sequencing, combined with functional imaging, to identify the circuit components of this neuroimmune axis, and showed that its selective manipulation can effectively suppress the pro-inflammatory response while enhancing an anti-inflammatory state. The brain-evoked transformation of the course of an immune response offers new possibilities in the modulation of a wide range of immune disorders, from autoimmune diseases to cytokine storm and shock.
10.1038/s41586-024-07469-y
Cell biology of inflammasome activation.
Pandey Abhimanu,Shen Cheng,Feng Shouya,Man Si Ming
Trends in cell biology
Organelles are critical structures in mediating the assembly and activation of inflammasomes in mammalian cells, resulting in inflammation and cell death. Assembly of inflammasomes can occur at the mitochondria, endoplasmic reticulum, nucleus, trans-Golgi network, or pathogen surface, facilitated by the overarching architecture of the cytoskeleton. NLRP3 and Pyrin inflammasome sensors may form smaller speckles and converge on a single larger speck at the microtubule-organizing center (MTOC). This signaling hub activates multiple mammalian inflammatory and apoptotic caspases, cytokine substrates, the pore-forming protein gasdermin D, and the plasma membrane rupture protein ninjurin-1 (NINJ1), allowing pyroptosis, cellular disintegration, and inflammation to ensue. In this review, we highlight the role of mammalian cell types and organellar architectures in executing inflammasome responses.
10.1016/j.tcb.2021.06.010
The pain of being sick: implications of immune-to-brain communication for understanding pain.
Watkins L R,Maier S F
Annual review of psychology
This review focuses on the powerful pain facilitatory effects produced by the immune system. Immune cells, activated in response to infection, inflammation, or trauma, release proteins called proinflammatory cytokines. These proinflammatory cytokines signal the central nervous system, thereby creating exaggerated pain as well as an entire constellation of physiological, behavioral, and hormonal changes. These changes are collectively referred to as the sickness response. Release of proinflammatory cytokines by immune cells in the body leads, in turn, to release of proinflammatory cytokines by glia within the brain and spinal cord. Evidence is reviewed supporting the idea that proinflammatory cytokines exert powerful pain facilitatory effects following their release in the body, in the brain, and in the spinal cord. Such exaggerated pain states naturally occur in situations involving infection, inflammation, or trauma of the skin, of peripheral nerves, and of the central nervous system itself. Implications for human pain conditions are discussed.
10.1146/annurev.psych.51.1.29
Interleukin-3 coordinates glial-peripheral immune crosstalk to incite multiple sclerosis.
Immunity
Glial cells and central nervous system (CNS)-infiltrating leukocytes contribute to multiple sclerosis (MS). However, the networks that govern crosstalk among these ontologically distinct populations remain unclear. Here, we show that, in mice and humans, CNS-resident astrocytes and infiltrating CD44CD4 T cells generated interleukin-3 (IL-3), while microglia and recruited myeloid cells expressed interleukin-3 receptor-ɑ (IL-3Rɑ). Astrocytic and T cell IL-3 elicited an immune migratory and chemotactic program by IL-3Rɑ myeloid cells that enhanced CNS immune cell infiltration, exacerbating MS and its preclinical model. Multiregional snRNA-seq of human CNS tissue revealed the appearance of IL3RA-expressing myeloid cells with chemotactic programming in MS plaques. IL3RA expression by plaque myeloid cells and IL-3 amount in the cerebrospinal fluid predicted myeloid and T cell abundance in the CNS and correlated with MS severity. Our findings establish IL-3:IL-3RA as a glial-peripheral immune network that prompts immune cell recruitment to the CNS and worsens MS.
10.1016/j.immuni.2023.04.013
Infiltrating CD8 T cells exacerbate Alzheimer's disease pathology in a 3D human neuroimmune axis model.
Nature neuroscience
Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8 T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.
10.1038/s41593-023-01415-3
Identification of Pathogenic Immune Cell Subsets Associated With Checkpoint Inhibitor-Induced Myocarditis.
Circulation
BACKGROUND:Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune-related adverse events such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T cell-mediated mechanisms. However, the precise pathological immune subsets and molecular changes in ICI myocarditis are unknown. METHODS:To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry on peripheral blood mononuclear cells from 52 individuals: 29 patients with autoimmune adverse events (immune-related adverse events) on ICI, including 8 patients with ICI myocarditis, and 23 healthy control subjects. We also used multiomics single-cell technology to immunophenotype 30 patients/control subjects using single-cell RNA sequencing, single-cell T-cell receptor sequencing, and cellular indexing of transcriptomes and epitopes by sequencing with feature barcoding for surface marker expression confirmation. To correlate between the blood and the heart, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing on MRL/Pdcd1 (Murphy Roths large/programmed death-1-deficient) mice with spontaneous myocarditis. RESULTS:Using these complementary approaches, we found an expansion of cytotoxic CD8 T effector cells re-expressing CD45RA (Temra CD8 cells) in patients with ICI myocarditis compared with control subjects. T-cell receptor sequencing demonstrated that these CD8 Temra cells were clonally expanded in patients with myocarditis compared with control subjects. Transcriptomic analysis of these Temra CD8 clones confirmed a highly activated and cytotoxic phenotype. Longitudinal study demonstrated progression of these Temra CD8 cells into an exhausted phenotype 2 months after treatment with glucocorticoids. Differential expression analysis demonstrated elevated expression levels of proinflammatory chemokines (CCL5/CCL4/CCL4L2) in the clonally expanded Temra CD8 cells, and ligand receptor analysis demonstrated their interactions with innate immune cells, including monocytes/macrophages, dendritic cells, and neutrophils, as well as the absence of key anti-inflammatory signals. To complement the human study, we performed single-cell RNA sequencing/T-cell receptor sequencing/cellular indexing of transcriptomes and epitopes by sequencing in Pdcd1 mice with spontaneous myocarditis and found analogous expansions of cytotoxic clonal effector CD8 cells in both blood and hearts of such mice compared with controls. CONCLUSIONS:Clonal cytotoxic Temra CD8 cells are significantly increased in the blood of patients with ICI myocarditis, corresponding to an analogous increase in effector cytotoxic CD8 cells in the blood/hearts of Pdcd1 mice with myocarditis. These expanded effector CD8 cells have unique transcriptional changes, including upregulation of chemokines CCL5/CCL4/CCL4L2, which may serve as attractive diagnostic/therapeutic targets for reducing life-threatening cardiac immune-related adverse events in ICI-treated patients with cancer.
10.1161/CIRCULATIONAHA.121.056730