Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Jiang, Wei; Li, Daojing; Han, Ranran; Zhang, Chao; Jin, Wei�; Wood, Kristofer; Liu, Qiang; Shi, Fu Dong; Hao, Junwei

doi:10.1073/pnas.1705491114

Cited by 66 publications

(69 citation statements)

References 68 publications

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“…They can be found throughout the cLP, and are efficient producers of inflammatory cytokines, such as TNF and IL-1b, that support pathogenic T cell responses in the intestine 33,54,55 (Fig 6). Being intimately related to MHCII + monocytes in the continuum of monocyte to macrophage differentiation, CD11c + macrophages are likely to represent what was previously described as monocytemacrophage intermediates and effector cells in multiple inflammatory disorders 56,57,58,59 .…”

Section: Discussionmentioning

confidence: 85%

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype

Corbin

Gomez-Vazquez

Khoyratty

et al. 2019

Preprint

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Mononuclear phagocytes (MNPs) play a key role in maintaining intestinal homeostasis but also in triggering immunopathology in response to acute microbial stimulation, which induces the recruitment of masses of Ly6C hi monocytes to the gut. The regulators that control monocyte tissue adaptation in the gut remain poorly understood. Interferon Regulatory Factor 5 (IRF5) is a transcription factor previously shown to play a key role in maintaining the inflammatory phenotype of macrophages. Here we investigate the impact of IRF5 on the MNP system and physiology of the gut at homeostasis and during inflammation. We demonstrate that IRF5 deficiency has a limited impact on colon physiology at steady state, but ameliorates immunopathology during Helicobacter hepaticus induced colitis. Inhibition of IRF5 activity in MNPs phenocopies global IRF5 deficiency. Using a combination of bone marrow chimera and single cell RNA-sequencing approaches we compare the differentiation trajectories of wild type and IRF5 deficient monocytes in a shared inflammatory environment and demonstrate that IRF5 stipulates a choice in monocyte differentiation towards macrophages. Specifically, IRF5 promotes the generation of pathogenic CD11c + macrophages and controls the production of inflammatory mediators by these cells. Thus, we identify IRF5 as a key transcriptional controller of pathogenic monocyte differentiation in the gut.

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Section: Discussionmentioning

confidence: 85%

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype

Corbin

Gomez-Vazquez

Khoyratty

et al. 2019

Preprint

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“…Alternatively, there may be an alternate source of acetylcholine in bone marrow cell cultures or in vivo, which could bind to the nAChR concomitantly with mecamylamine. Although acetylcholine is abundantly produced in the CNS, its production has also been demonstrated in non-neuronal cells, such as T cells [ 63 – 67 ], natural killer cells [ 68 ] and endothelial cells [ 69 ]. Treatment of BMDMs or mice with mecamylamine in the presence of local acetylcholine production could therefore be sufficient to modulate inflammatory responses.…”

Section: Discussionmentioning

confidence: 99%

A silent agonist of α7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE

Godin

Roy

Quadri

et al. 2020

Brain, Behavior, and Immunity

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Nicotinic acetylcholine receptors (nAChRs) are best known to function as ligand-gated ion channels in the nervous system. However, recent evidence suggests that nicotine modulates inflammation by desensitizing non-neuronal nAChRs, rather than by inducing channel opening. Silent agonists are molecules that selectively induce the desensitized state of nAChRs while producing little or no channel opening. A silent agonist of α7 nAChRs has recently been shown to reduce inflammation in an animal model of inflammatory pain. The objective of this study was to determine whether a silent agonist of α7 nAChRs can also effectively modulate inflammation and disease manifestation in an animal model of multiple sclerosis. We first evaluated the effects of various nAChR ligands and of an α7 nAChR-selective silent agonist, 1-ethyl-4-(3-(bromo)phenyl)piperazine (m-bromo PEP), on the modulation of mouse bone marrow-derived monocyte/macrophage (BMDM) numbers, phenotype and cytokine production. The non-competitive antagonist mecamylamine and the silent agonist m-bromo PEP reduced pro-inflammatory BMDM numbers by affecting their viability and proliferation. Both molecules also significantly reduced cytokine production by mouse BMDMs and significantly ameliorated disease in experimental autoimmune encephalomyelitis. Finally, m-bromo PEP also reduced chronic inflammatory pain in mice. Taken together, our results further support the hypothesis that nAChRs may modulate inflammation via receptor desensitization rather than channel opening. α7 nAChR-selective silent agonists may thus be a novel source of anti-inflammatory compounds that could be used for the treatment of inflammatory disorders.

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“…Immunological synapse formation leads to polarization of NK cells towards their target synapse, followed by lysosomal docking at the plasma membrane and finally the fusion and release of contents 61 . NK cell function extends beyond malignant cell lysis with various roles, such as antimicrobial defense 64,65 , formation of immunological memory 66 , resolution of inflammation [67][68][69][70] , and endocytosis of extracellular proteins 24,71 .…”

Section: Properties Of Nk Cellsmentioning

confidence: 99%

The role of natural killer cells in Parkinson’s disease

Earls

Lee

2020

Exp Mol Med

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Numerous lines of evidence indicate an association between sustained inflammation and Parkinson’s disease, but whether increased inflammation is a cause or consequence of Parkinson’s disease remains highly contested. Extensive efforts have been made to characterize microglial function in Parkinson’s disease, but the role of peripheral immune cells is less understood. Natural killer cells are innate effector lymphocytes that primarily target and kill malignant cells. Recent scientific discoveries have unveiled numerous novel functions of natural killer cells, such as resolving inflammation, forming immunological memory, and modulating antigen-presenting cell function. Furthermore, natural killer cells are capable of homing to the central nervous system in neurological disorders that exhibit exacerbated inflammation and inhibit hyperactivated microglia. Recently, a study demonstrated that natural killer cells scavenge alpha-synuclein aggregates, the primary component of Lewy bodies, and systemic depletion of natural killer cells results in exacerbated neuropathology in a mouse model of alpha-synucleinopathy, making them a highly relevant cell type in Parkinson’s disease. However, the exact role of natural killer cells in Parkinson’s disease remains elusive. In this review, we introduce the systemic inflammatory process seen in Parkinson’s disease, with a particular focus on the direct and indirect modulatory capacity of natural killer cells in the context of Parkinson’s disease.

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Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Cited by 66 publications

References 68 publications

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype

A silent agonist of α7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE

The role of natural killer cells in Parkinson’s disease

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Acetylcholine-producing NK cells attenuate CNS inflammation via modulation of infiltrating monocytes/macrophages

Cited by 66 publications

References 68 publications

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+macrophage phenotype

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c+macrophage phenotype

A silent agonist of α7 nicotinic acetylcholine receptors modulates inflammation ex vivo and attenuates EAE

The role of natural killer cells in Parkinson’s disease

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Product

Resources

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IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype

IRF5 promotes intestinal inflammation by guiding monocyte differentiation towards a pathogenic CD11c⁺macrophage phenotype