IL-17 and IL-17-producing cells in protection versus pathology

Mills, Kingston H. G.

doi:10.1038/s41577-022-00746-9

Cited by 420 publications

(282 citation statements)

References 244 publications

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“…The accumulated evidence demonstrates that γδT17 cells play a central role in the pathogenesis of psoriatic dermatitis ( 1 ). We examined the significance of the role of Syk in the inflammatory condition by use of an imiquimod (IMQ)-induced psoriasis model.…”

Section: Resultsmentioning

confidence: 99%

“…γδT cells exert multiple functions while acting as innate effector cells that produce cytokines and/or kill infected or malignant cells. Recently, accumulating evidence has suggested the versatile roles played by a subset of IL-17-producing γδT cells (γδT17 cells) in inflammatory disorders ( 1 ), tumor progression ( 2 ), tissue regeneration ( 3 – 5 ), and fibrosis ( 6 ) as well as affording protection from bacterial and fungal infection ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation

et al. 2023

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The γδT cells that produce IL-17 (γδT17 cells) play a key role in various pathophysiologic processes in host defense and homeostasis. The development of γδT cells in the thymus requires γδT cell receptor (γδTCR) signaling mediated by the spleen tyrosine kinase (Syk) family proteins, Syk and Zap70. Here, we show a critical role of Syk in the early phase of γδT cell development using mice deficient for Syk specifically in lymphoid lineage cells (Syk-conditional knockout (cKO) mice). The development of γδT cells in the Syk-cKO mice was arrested at the precursor stage where the expression of Rag genes and αβT-lineage-associated genes were retained, indicating that Syk is required for γδT-cell lineage commitment. Loss of Syk in γδT cells weakened TCR signal-induced phosphorylation of Erk and Akt, which is mandatory for the thymic development of γδT17 cells. Syk-cKO mice exhibited a loss of γδT17 cells in the thymus as well as throughout the body, and thereby are protected from γδT17-dependent psoriasis-like skin inflammation. Collectively, our results indicate that Syk is a key player in the lineage commitment of γδT cells and the priming of γδT17 cell differentiation.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation

et al. 2023

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“…Chemokines play a key role in the neutrophil recruitment to the inflamed tissues ( 27 ). One of the factors able to control chemokine production in these tissues is IL-17 ( 28 ). Indeed, IL-17A/F levels were increased in the lysates prepared from footpads of Pstpip2 cmo mice ( Figure 4C ).…”

Section: Resultsmentioning

confidence: 99%

Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation

et al. 2022

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IntroductionAutoinflammatory diseases are characterized by dysregulation of innate immune system leading to spontaneous sterile inflammation. One of the well-established animal models of this group of disorders is the mouse strain Pstpip2cmo. In this strain, the loss of adaptor protein PSTPIP2 leads to the autoinflammatory disease chronic multifocal osteomyelitis. It is manifested by sterile inflammation of the bones and surrounding soft tissues of the hind limbs and tail. The disease development is propelled by elevated production of IL-1β and reactive oxygen species by neutrophil granulocytes. However, the molecular mechanisms linking PSTPIP2 and these pathways have not been established. Candidate proteins potentially involved in these mechanisms include PSTPIP2 binding partners, PEST family phosphatases (PEST-PTPs) and phosphoinositide phosphatase SHIP1.MethodsTo address the role of these proteins in PSTPIP2-mediated control of inflammation, we have generated mouse strains in which PEST-PTP or SHIP1 binding sites in PSTPIP2 have been disrupted. In these mouse strains, we followed disease symptoms and various inflammation markers.ResultsOur data show that mutation of the PEST-PTP binding site causes symptomatic disease, whereas mice lacking the SHIP1 interaction site remain asymptomatic. Importantly, both binding partners of PSTPIP2 contribute equally to the control of IL-1β production, while PEST-PTPs have a dominant role in the regulation of reactive oxygen species. In addition, the interaction of PEST-PTPs with PSTPIP2 regulates the production of the chemokine CXCL2 by neutrophils. Its secretion likely creates a positive feedback loop that drives neutrophil recruitment to the affected tissues.ConclusionsWe demonstrate that PSTPIP2-bound PEST-PTPs and SHIP1 together control the IL-1β pathway. In addition, PEST-PTPs have unique roles in the control of reactive oxygen species and chemokine production, which in the absence of PEST-PTP binding to PSTPIP2 shift the balance towards symptomatic disease.

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“…One such possibility examined is the role of a different proinflammatory cytokine, IL-17. IL-17, important for protection against various extracellular mucosal pathogens, is derived from innate and adaptive lymphocytes ( Mills, 2022 ). IL-17 is involved in neutrophil recruitment and promotes IL-22 and antimicrobial peptide production ( Mills, 2022 ).…”

Section: Brucella Immunologymentioning

confidence: 99%

“…IL-17, important for protection against various extracellular mucosal pathogens, is derived from innate and adaptive lymphocytes ( Mills, 2022 ). IL-17 is involved in neutrophil recruitment and promotes IL-22 and antimicrobial peptide production ( Mills, 2022 ). Although often overlooked, IL-17 has had varied impact on protection against brucellosis, but IL-17 may be more relevant upon extracellular brucellae release from killed host cells.…”

Section: Brucella Immunologymentioning

confidence: 99%

Activation of mucosal immunity as a novel therapeutic strategy for combating brucellosis

et al. 2022

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Brucellosis is a disease of livestock that is commonly asymptomatic until an abortion occurs. Disease in humans results from contact of infected livestock or consumption of contaminated milk or meat. Brucella zoonosis is primarily caused by one of three species that infect livestock, Bacillus abortus in cattle, B. melitensis in goats and sheep, and B. suis in pigs. To aid in disease prophylaxis, livestock vaccines are available, but are only 70% effective; hence, improved vaccines are needed to mitigate disease, particularly in countries where disease remains pervasive. The absence of knowing which proteins confer complete protection limits development of subunit vaccines. Instead, efforts are focused on developing new and improved live, attenuated Brucella vaccines, since these mimic attributes of wild-type Brucella, and stimulate host immune, particularly T helper 1-type responses, required for protection. In considering their development, the new mutants must address Brucella’s defense mechanisms normally active to circumvent host immune detection. Vaccination approaches should also consider mode and route of delivery since disease transmission among livestock and humans is believed to occur via the naso-oropharyngeal tissues. By arming the host’s mucosal immune defenses with resident memory T cells (TRMs) and by expanding the sources of IFN-γ, brucellae dissemination from the site of infection to systemic tissues can be prevented. In this review, points of discussion focus on understanding the various immune mechanisms involved in disease progression and which immune players are important in fighting disease.

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IL-17 and IL-17-producing cells in protection versus pathology

Cited by 420 publications

References 244 publications

Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation

Spleen tyrosine kinase mediates the γδTCR signaling required for γδT cell commitment and γδT17 differentiation

Molecular interactions of adaptor protein PSTPIP2 control neutrophil-mediated responses leading to autoinflammation

Activation of mucosal immunity as a novel therapeutic strategy for combating brucellosis

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