The IL-17 family is an evolutionarily old cytokine family consisting of six members (IL-17A through IL-17F). IL-17 family cytokines signal through heterodimeric receptors that include the shared ...IL-17RA subunit, which is widely expressed throughout the body on both hematopoietic and nonhematopoietic cells. The founding family member, IL-17A, is usually referred to as IL-17 and has received the most attention for proinflammatory roles in autoimmune diseases like psoriasis. However, IL-17 is associated with a wide array of diseases with perhaps surprisingly variable pathologies. This review focuses on recent advances in the roles of IL-17 during health and in disease pathogenesis. To decipher the functions of IL-17 in diverse disease processes it is useful to first consider the physiological functions that IL-17 contributes to health. We then discuss how these beneficial functions can be diverted toward pathogenic amplification of deleterious pathways driving chronic disease.
IL-17 is a highly versatile pro-inflammatory cytokine crucial for a variety of processes, including host defense, tissue repair, the pathogenesis of inflammatory disease and the progression of ...cancer. In contrast to its profound impact in vivo, IL-17 exhibits surprisingly moderate activity in cell-culture models, which presents a major knowledge gap about the molecular mechanisms of IL-17 signaling. Emerging studies are revealing a new dimension of complexity in the IL-17 pathway that may help explain its potent and diverse in vivo functions. Discoveries of new mRNA stabilizers and receptor-directed mRNA metabolism have provided insights into the means by which IL-17 cooperates functionally with other stimuli in driving inflammation, whether beneficial or destructive. The integration of IL-17 with growth-receptor signaling in specific cell types offers new understanding of the mitogenic effect of IL-17 on tissue repair and cancer. This Review summarizes new developments in IL-17 signaling and their pathophysiological implications.
Changing behind the scenes McGeachy, Mandy J.
The Journal of experimental medicine,
08/2024, Letnik:
221, Številka:
8
Journal Article
Recenzirano
Th17 cell plasticity is associated with pathogenicity in chronic inflammation. In a model of periodontitis, McClure et al. (https://doi.org/10.1084/jem.20232015) describe location-dependent ...divergence in Th17 plasticity, with surprisingly limited conversion in inflamed gingiva but emergence of protective exTh17-TfH cells in draining LN that enhance protective antibody.
IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse ...periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.
IL-23 activates pathogenic Th17 cells to drive inflammatory disease at barrier surfaces. Kim et al. now identify oral epithelial cells as the critical producers of IL-23 in human and mouse periodontitis, linking microbial dysbiosis to non-hematopoietic regulation of IL-17-associated inflammation.
The 'silent epidemic' of traumatic brain injury (TBI) has been placed in the spotlight as a result of clinical investigations and popular press coverage of athletes and veterans with single or ...repetitive head injuries. Neuroinflammation can cause acute secondary injury after TBI, and has been linked to chronic neurodegenerative diseases; however, anti-inflammatory agents have failed to improve TBI outcomes in clinical trials. In this Review, we therefore propose a new framework of targeted immunomodulation after TBI for future exploration. Our framework incorporates factors such as the time from injury, mechanism of injury, and secondary insults in considering potential treatment options. Structuring our discussion around the dynamics of the immune response to TBI - from initial triggers to chronic neuroinflammation - we consider the ability of soluble and cellular inflammatory mediators to promote repair and regeneration versus secondary injury and neurodegeneration. We summarize both animal model and human studies, with clinical data explicitly defined throughout this Review. Recent advances in neuroimmunology and TBI-responsive neuroinflammation are incorporated, including concepts of inflammasomes, mechanisms of microglial polarization, and glymphatic clearance. Moreover, we highlight findings that could offer novel therapeutic targets for translational and clinical research, assimilate evidence from other brain injury models, and identify outstanding questions in the field.
Excessive collagen deposition by fibroblasts surrounding some tumors has seriously limited the efficacy of checkpoint inhibitor therapies. Chen et al. (2022. J. Exp. ...Med.https://doi.org/10.1084/jem.20210693) show that IL-17 promotes collagen deposition by cancer-associated fibroblasts, enhancing immune exclusion of tumors, and that targeting IL-17-triggered HIF1α expression can reverse matrix mediated immune exclusion.
IL-17 was discovered nearly 30 yr ago, but it has only been recently appreciated that a key function of this cytokine is to orchestrate cellular and organismal metabolism. Indeed, metabolic ...regulation is integrated into both the physiological and the pathogenic aspects of IL-17 responses. Thus, understanding the interplay between IL-17 and downstream metabolic processes could ultimately inform therapeutic opportunities for diseases involving IL-17, including some not traditionally linked to this cytokine pathway. Here, we discuss the emerging pathophysiological roles of IL-17 related to cellular and organismal metabolism, including metabolic regulation of IL-17 signal transduction.
Identification of the pathogenic cytokines that underlie the IL-23-dependent disease progression of experimental autoimmune encephalomyelitis has proven elusive. Evidence now points to GM-CSF.
This Pillars of Immunology article is a commentary on “Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer ...cells,” a pivotal article written by S. F. Wolf, P. A. Temple, M. Kobayashi, D. Young, M. Dicig, L. Lowe, R. Dzialo, L. Fitz, C. Ferenz, R. M. Hewick, et al., and published in The Journal of Immunology, in 1991. https://doi.org/10.4049/jimmunol.146.9.3074.
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections; therefore, constraint of this pathway is an essential component of its regulation. We demonstrate that the signaling ...intermediate MCPIP1 (also termed Regnase-1, encoded by Zc3h12a) is a feedback inhibitor of IL-17 receptor signal transduction. MCPIP1 knockdown enhanced IL-17-mediated signaling, requiring MCPIP1’s endoribonuclease but not deubiquitinase domain. MCPIP1 haploinsufficient mice showed enhanced resistance to disseminated Candida albicans infection, which was reversed in an Il17ra−/− background. Conversely, IL-17-dependent pathology in Zc3h12a+/− mice was exacerbated in both EAE and pulmonary inflammation. MCPIP1 degraded Il6 mRNA directly but only modestly downregulated the IL-6 promoter. However, MCPIP1 strongly inhibited the Lcn2 promoter by regulating the mRNA stability of Nfkbiz, encoding the IκBζ transcription factor. Unexpectedly, MCPIP1 degraded Il17ra and Il17rc mRNA, independently of the 3′ UTR. The cumulative impact of MCPIP1 on IL-6, IκBζ, and possibly IL-17R subunits results in a biologically relevant inhibition of IL-17 signaling.
Display omitted
•MCPIP1 (Regnase-1) is a feedback inhibitor of IL-17 signal transduction•MCPIP1 deficiency enhances immunity to fungi but exacerbates pathology in EAE•MCPIP1 impairs activation of certain IL-17 target promoters by degrading IκBζ mRNA•MCPIP1 degrades transcripts encoding IL-17R subunits independently of the 3′ UTR
Interleukin-17 (IL-17) induces pathology in autoimmunity and infections and therefore its activity must be tightly regulated. Gaffen and colleagues report that the endoribonuclease MCPIP1 degrades IL-17-induced transcripts, including Il6 and Nfkbiz (Iκβζ), to negatively regulate IL-17 receptor signaling both in fungal immunity and experimental autoimmune encephalomyelitis.