NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Louis, Cynthia; Souza-Fonseca-Guimarães, Fernando; Yang, Yuyan; D'Silva, Damian B; Kratina, Tobias; Dagley, Laura F.; Hediyeh-Zadeh, Soroor; Rautela, Jai; Masters, Seth L.; Davis, Melissa J.; Babon, Jeffrey J.; Ćirić, Bogoljub; Vivier, Éric; Alexander, Warren S.; Huntington, Nicholas; Wicks, Ian P.

doi:10.1084/jem.20191421

Cited by 67 publications

(86 citation statements)

References 113 publications

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“…More recently, we reported that synovial joint NK cells propagate joint inflammation by secreting the pro‐inflammatory cytokine GM‐CSF 91 (Figure 1b). This occurs in an IL‐18‐dependent manner, and independently of their cytotoxic function or IFN‐γ production 91 . GM‐CSF, in turn, signals to joint‐infiltrating myeloid cells such as neutrophils to upregulate pro‐inflammatory CXCL2, CCL3 and LTβ4, thereby sustaining immune cell recruitment into inflamed joints 91 .…”

Section: Nk Cells In Rheumatoid Arthritismentioning

confidence: 85%

“…Synovial NK‐derived IFN‐γ has also been thought to limit arthritis by inhibiting Th17 polarisation in the CIA model, 100 but this seems questionable given the low IFN‐γ production by RA synovial NK cells 115 . More recently, we reported that synovial joint NK cells propagate joint inflammation by secreting the pro‐inflammatory cytokine GM‐CSF 91 (Figure 1b). This occurs in an IL‐18‐dependent manner, and independently of their cytotoxic function or IFN‐γ production 91 .…”

Section: Nk Cells In Rheumatoid Arthritismentioning

confidence: 97%

“…Furthermore, NK cells found in target non‐lymphoid tissues, such as the inflamed joint of RA patients, 81,82 the central nervous system (CNS) of MS patients, 83 and the inflamed skin of psoriasis patients, 80 were found to produce high levels of pro‐inflammatory cytokines including IFN‐γ and tumor necrosis factor‐α (TNF‐α). In addition to IFN‐γ and TNF‐α, NK cells may also secrete other cytokines such as granulocyte/macrophage‐colony stimulating factor (GM‐CSF), macrophage‐colony stimulating factor (M‐CSF), IL‐5, IL‐10, IL‐13, and chemokines CCL3, CCL4, CCL5, IL‐8, RANTES and XCL1 83–92 …”

Section: Immune Regulatory Functions Of Nk Cellsmentioning

confidence: 99%

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Natural killer cells in inflammatory autoimmune diseases

et al. 2021

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Natural killer (NK) cells are a specialised population of innate lymphoid cells (ILCs) that help control local immune responses. Through natural cytotoxicity, production of cytokines and chemokines, and migratory capacity, NK cells play a vital immunoregulatory role in the initiation and chronicity of inflammatory and autoimmune responses. Our understanding of their functional differences and contributions in disease settings is evolving owing to new genetic and functional murine proof‐of‐concept studies. Here, we summarise current understanding of NK cells in several classic autoimmune disorders, particularly in rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM), but also less understood diseases such as idiopathic inflammatory myopathies (IIMs). A better understanding of how NK cells contribute to these autoimmune disorders may pave the way for NK cell‐targeted therapeutics.

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Section: Nk Cells In Rheumatoid Arthritismentioning

confidence: 85%

Section: Nk Cells In Rheumatoid Arthritismentioning

confidence: 97%

Section: Immune Regulatory Functions Of Nk Cellsmentioning

confidence: 99%

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Natural killer cells in inflammatory autoimmune diseases

et al. 2021

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“…This has been suggested to occur through NK cell production of GM-CSF ( 7 , 8 ). That GM-CSF produced by NK cells has been shown to potentiate several chronic inflammatory disorders ( 9 ) may indicate involvement of NK cell-neutrophil crosstalk in these diseases. NK cells recruit neutrophils to inflammatory sites through several mechanisms, including the CCL3-CCR5 signaling axis ( 2 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Docosahexaenoic Acid Modulates NK Cell Effects on Neutrophils and Their Crosstalk

et al. 2020

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Natural killer (NK) cells and neutrophils engage in crosstalk that is important in inflammation and likely also for resolution of inflammation. NK cells activate neutrophils and induce their infiltration to the inflamed sites but may also influence their apoptosis and their subsequent efferocytosis by macrophages. Several studies indicate that docosahexaenoic acid (DHA) can inhibit NK cell cytotoxicity but the effects of DHA on the ability of NK cells to engage in crosstalk with neutrophils and affect their functions have not been described. This study explored the kinetics of the effects of NK cells and NK cells pre-treated with DHA on neutrophil surface molecule expression and apoptosis, as well as the ability of NK cells to affect other neutrophil functions. In addition, the study explored the effects of neutrophils on NK cell phenotype and function. Primary NK cells were pre-incubated with or without DHA, then stimulated and co-cultured with freshly isolated neutrophils. When co-cultured with NK cells, neutrophils had higher expression levels of CD11b and CD47; secreted more IL-8, IL-1ra, and CXCL10; had increased phagocytic ability; and their apoptosis was increased early after initiation of the co-culture while dampened at a later time-point. Pre-incubation of NK cells with DHA attenuated NK cell-induced upregulation of CD11b and CD47 on neutrophils, had minor effects on NK cell induction of cytokine/chemokine secretion or their phagocytic ability. Neutrophils also affected the function of NK cells, lowering the frequency of NKp46 + and CXCR3 + NK cells and increasing the concentrations of IFN-γ, TNF-α, and GM-CSF in the co-cultures. Pre-incubation of NK cells with DHA further decreased the frequency of NKp46 + NK cells in the co-culture with neutrophils and decreased the concentrations of IFN-γ, CCL3 and GM-CSF. These findings indicate that NK cells have mostly pro-inflammatory effects on neutrophils and that DHA can attenuate some of these pro-inflammatory effects. Neutrophils had both anti- and pro-inflammatory effects on NK cells. When NK cells had been pre-treated with DHA, the anti-inflammatory effects were increased and some of the pro-inflammatory effects attenuated. Overall, the results suggest that DHA may lead to a more anti-inflammatory microenvironment for NK cell and neutrophil crosstalk.

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“…For example, NK cell production of IFN-γ is critical for the complete elimination of intracellular bacteria by myeloid cells ( Dunn and North, 1991 ; Feng et al, 2006 ; Steinhoff et al, 1991 ). NK cells can also control macrophage polarization in adipose tissue ( Lee et al, 2016 ; O’Sullivan et al, 2016 ), recruit dendritic cells (DCs) to tumors ( Barry et al, 2018 ; Böttcher et al, 2018 ), and promote neutrophil infiltration into inflamed joints ( Louis et al, 2020 ). On the other hand, NK cells have also been shown to modulate CD4 + T and CD8 + T cell responses in a variety of contexts, ranging from directly pruning activated CD4 + T cells to preventing exaggerated CD8 + T cell responses ( Lang et al, 2012 ; Schuster et al, 2014 ; Waggoner et al, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

Coordinated Viral Control by Cytotoxic Lymphocytes Ensures Optimal Adaptive NK Cell Responses

Díaz-Salazar

Sun

2020

Cell Reports

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SUMMARY Natural killer (NK) cells play a critical role in controlling viral infections, coordinating the response of innate and adaptive immune systems. They also possess certain features of adaptive lymphocytes, such as undergoing clonal proliferation. However, it is not known whether this adaptive NK cell response can be modulated by other lymphocytes during viral exposure. Here, we show that the clonal expansion of NK cells during mouse cytomegalovirus infection is severely blunted in the absence of cytotoxic CD8 + T cells. This correlates with higher viral burden and an increased pro-inflammatory milieu, which maintains NK cells in a hyper-activated state. Antiviral therapy rescues NK cell expansion in the absence of CD8 + T cells, suggesting that high viral loads have detrimental effects on adaptive NK cell responses. Altogether, our data support a mechanism whereby cytotoxic innate and adaptive lymphocytes cooperate to ensure viral clearance and the establishment of robust clonal NK cell responses.

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NK cell–derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS

Cited by 67 publications

References 113 publications

Natural killer cells in inflammatory autoimmune diseases

Natural killer cells in inflammatory autoimmune diseases

Docosahexaenoic Acid Modulates NK Cell Effects on Neutrophils and Their Crosstalk

Coordinated Viral Control by Cytotoxic Lymphocytes Ensures Optimal Adaptive NK Cell Responses

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