Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia, Nicola; Arruda‐Silva, Fabio; Wright, Helen L.; Moots, Robert J.; Gardiman, Elisa; Bianchetto-Aguilera, Francisco M.; Gasperini, Sara; Capone, Manuela; Maggi, Laura; Annunziato, Francesco; Edwards, Steven W.; Cassatella, Marco A.

doi:10.1002/jlb.ma0818-308r

Cited by 35 publications

(43 citation statements)

References 56 publications

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“…Of note, these results were validated by qPCR of selected key genes. Recently, Tamassia et al reported that the use of Adalimumab decreased the production of IL-23 protein as well as decreased levels of IL12B and IL23A transcripts in TLR-8 activated neutrophils (47). Indeed, the gene-expression profiling predicts a net effect of potent anti-inflammatory action by Adalimumab.…”

Section: Discussionmentioning

confidence: 99%

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

et al. 2020

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Accumulation of activated neutrophils at the feto-maternal interface is a defining hallmark of intrauterine inflammation (IUI) that might trigger an excessive immune response during pregnancy. Mechanisms responsible of this massive neutrophil recruitment are poorly investigated. We have previously showed that intraamniotic injection of LPS in rhesus macaques induced a neutrophil predominant inflammatory response similar to that seen in human IUI. Here, we demonstrate that anti-TNF antibody (Adalimumab) inhibited ∼80% of genes induced by LPS involved in inflammatory signaling and innate immunity in chorio-decidua neutrophils. Consistent with the gene expression data, TNF-blockade decreased LPS-induced neutrophil accumulation and activation at the feto-maternal interface. We also observed a reduction in IL-6 and other pro-inflammatory cytokines but not prostaglandins concentrations in the amniotic fluid. Moreover, TNF-blockade decreased mRNA expression of inflammatory cytokines in the chorio-decidua but not in the uterus, suggesting that inhibition of TNF-signaling decreased the inflammation in a tissue-specific manner within the uterine compartment. Taken together, our results demonstrate a predominant role for TNF-signaling in modulating the neutrophilic infiltration at the feto-maternal interface during IUI and suggest that blockade of TNF-signaling could be considered as a therapeutic approach for IUI, the major leading cause of preterm birth.

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Section: Discussionmentioning

confidence: 99%

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

et al. 2020

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“…Mouse models of enthesitis also shown neutrophil infiltration . A recent human in vitro study showed that neutrophils showed greatest IL‐23 production when stimulated with TLR7/8 agonists as opposed to TLR4 . The physiological importance of neutrophil‐derived IL‐23, however, must be treated with caution.…”

Section: The Concept Of Il‐23–independent Il‐17 Productionmentioning

confidence: 99%

“…140 A recent human in vitro study showed that neutrophils showed greatest IL-23 production when stimulated with TLR7/8 agonists as opposed to TLR4. 141 The physiological importance of neutrophil-derived IL-23, however, must be treated with caution. A psoriasis mouse model that utilizes imiquimod (TLR7/8) agonist is dependent on IL-23 production in monocytes and not neutrophils.…”

Section: Myeloid Cells As Producers Of Il-23 In Manmentioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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“…Neutrophils also produce the Th17 differentiation cytokine IL-23 [36], their elastase release processes DC-derived CXCL8 into a Th17-promoting form [37], and in vitro they can induce Th17 differentiation directly [38]. However, the mechanisms through which this occurs largely remain unknown.…”

Section: Introductionmentioning

confidence: 99%

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

Minns

Smith

Alessandrini

et al. 2020

Preprint

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The host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic cell death; it has potent antibacterial, antiviral and antifungal activity as well as being a powerful immunomodulator. It is released in proximity to CD4 + T cells during inflammatory and infectious disease but its impact on T cell phenotype is scarcely understood. Here we demonstrate that cathelicidin is a powerful Th17 potentiating factor which increases expression of the aryl hydrocarbon receptor (AHR) and the RORγt transcription factor, in a TGF-β1-dependent manner. We show that cathelicidin induces IL-17F production in particular, and that its induction of IL-17A+F+ double producing cells is dependent on AHR while its induction of IL-17F single producing cells is not. In the presence of TGF-β1, cathelicidin profoundly suppressed IL-2 and down-regulated T-bet, specifically directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1 cells were protected from apoptotic death by cathelicidin, in the first example of a neutrophil-released mediator inducing survival of a T cell subset. Finally, we show that cathelicidin is released by neutrophils in mouse lymph nodes following inoculation of heat-killed Salmonella typhimurium and that cathelicidin-deficient mice have suppressed Th17 responses during inflammation, but not at steady state. We propose that the release of cathelicidin by neutrophils is required for maximal Th17 differentiation and IL-17 production by CD4 + T cells, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses with some sophistication.

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Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Cited by 35 publications

References 56 publications

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

TNF-Signaling Modulates Neutrophil-Mediated Immunity at the Feto-Maternal Interface During LPS-Induced Intrauterine Inflammation

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

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