Psarras, Antonios

Richmond, Jillian M.

White, Wendy I.

English

Oxford University Research Archive

TYPE EditorialPUBLISHED 20 August 2024| DOI 10.3389/flupu.2024.1465771EDITED AND REVIEWED BYAntonio La Cava,University of California, Los Angeles,United States*CORRESPONDENCEWendy I. Whitersw2600@gmail.comJillian M. Richmondjillian.richmond@umassmed.edAntonios Psarrasantony.psarras@kennedy.ox.ac.ukRECEIVED 16 July 2024ACCEPTED 06 August 2024PUBLISHED 20 August 2024CITATIONWhite WI, Richmond JM and Psarras A (2024)Editorial: New insights into interferons andproinflammatory cytokines in lupus.Front. Lupus 2:1465771.doi: 10.3389/flupu.2024.1465771COPYRIGHT© 2024 White, Richmond and Psarras. This isan open-access article distributed under theterms of the Creative Commons AttributionLicense (CC BY). The use, distribution orreproduction in other forums is permitted,provided the original author(s) and thecopyright owner(s) are credited and that theoriginal publication in this journal is cited, inaccordance with accepted academic practice.No use, distribution or reproduction ispermitted which does not comply with theseterms.Frontiers in LupusEditorial: New insights intointerferons and proinflammatorycytokines in lupusWendy I. White1*, Jillian M. Richmond2* and Antonios Psarras3*1AstraZeneca (United States), Gaithersburg, MD, United States, 2Department of Dermatology, Universityof Massachusetts Medical School, Worcester, MA, United States, 3Kennedy Institute of Rheumatology,NDORMS, University of Oxford, Oxford, United KingdomKEYWORDSLupus (SLE), biomarker, chemokine, cytokine - immunological terms, inflammationEditorial on the Research TopicNew insights into interferons and proinflammatory cytokines in lupusSystemic lupus erythematosus (SLE) is a highly heterogenous disease that we are stillstruggling to fully understand. The alterations to the immune system also impact non-immune cells such as endothelial cells and fibroblasts. The interactions of the variouscell types are largely orchestrated by soluble mediators. In this collection, theinvestigators enhance our knowledge on some of these mediators, their intracellularsignaling events and ways of using the new information for drug development andbetter patient stratification.Nikolopoulos and Parodis reviewed the potential of targeting janus kinases (JAKs) forthe treatment of SLE. JAKs are intracellular tyrosine kinases that along with tyrosinekinase 2 (TYK2) mediate signaling via phosphorylation of signal transducer andactivators of transcription (STAT) proteins. Many cytokines use common JAK/STATpathways; hence, JAK/STAT inhibition could potentially interfere with the productionof several cytokine networks. The authors point out that TYK2 is part of the signalingcascade of several cytokines (IFNα, IL-6, IL-10 and IL-12/23) involved in thepathogenesis of SLE and that a selective inhibitor of TYK2 is currently in phase 3 trialsin patients with non-renal lupus. This review discusses mouse model data of variousdrugs that inhibit different combinations of JAKs or TYK2. It also covers experimentaldata on human cell in vitro studies and results from the limited (to date) clinical trials.Tang et al. reviewed the role of Th1 cells and associated cytokines in SLE. The authorssummarize several studies demonstrating that SLE patients vary in the number andpercentages of Th1 cells depending on different treatments and/or organ involvement.SLE patients have higher levels of Th1-related cytokines, such as IL-12 and IFN-γ, thanhealthy controls and higher levels are found in active than inactive disease. T-bet is alsofound in other immune cells including B cells. Patients with higher proportions ofT-bet+ naïve B cells had higher SLEDAI scores with higher ANA and anti-dsDNAlevels associated with shorter disease duration. The authors also summarize the use oflow dose IL-2 as a therapy for SLE. Interestingly, IL-2 therapy was associated withhigher SRI-4 responses in patients with low baseline Tregs. The reduction in Tregs-commonly reported with prednisolone therapy- was not observed in patients whoreceived low dose IL-2 treatment. These results, along with preliminary therapeutic01 frontiersin.orgWhite et al. 10.3389/flupu.2024.1465771benefit of low dose IL-2, suggest that the role of Th1 immunity inSLE deserves further study.In their original paper, Wang et al. show that the transcriptionfactor FLI-1 promotes CXCL10 in endothelial cells and itsreceptor (CXCR3) expression in T cells. Elevated levels of FLI-1are associated with active human lupus nephritis, whilst reductionof expression of FLI-1 in two lupus prone mouse strains decreasedrenal disease and prolonged mice’s survival through a reduction ininflammatory cell levels. In vitro experiments using both humanand mouse cells showed that transfection of FLI-1 siRNA greatlyreduced CXCL10 expression. However, FLI-1 failed to directlyactivate the CXCL10 promotor, thus the exact mechanism ofCXCL10 production remains unclear. Given FLI-1 is a keyregulator of other inflammatory cytokines, a greater understandingof the possible therapeutic benefit of its inhibition is warranted.The type I IFN pathway is known to be upregulated in a largeproportion of SLE patients. However, its role in primary andsecondary antiphospholipid syndrome (APS) is less understood.Cecchi et al. investigate the possible association between typeI IFN dysfunction and the disease state in asymptomaticindividuals with antiphospholipid antibodies (aPL) and APSpatients. SLE patients and healthy subjects without aPL are usedas control groups. Seven interferon stimulated genes (ISGs) wereevaluated in whole blood to produce a composite IFN score.Significant IFN activation was observed across the APS spectrum,although the exact level of the individual gene expression and theIFN score varied. This was found even in patients who did notmeet the clinical criteria of APS but had persistently positiveaPL. SLE patients displayed the highest and most consistentactivation. Thrombosis reoccurrence was positively associatedwith certain ISGs in patients with secondary APS (having bothAPS and SLE). The elevated presence of ISGs in patients onlyhaving aPL may represent a potential biomarker to stratify highrisk for thrombosis patients.An intriguing interplay of different type I interferons incutaneous lupus erythematosus (CLE) was uncovered by Xu et al.The researchers had previously shown that IFN-κ wasoverexpressed in lesional and non-lesional CLE keratinocytescontributing to photosensitivity, but the key mechanisms for thereported IFN-κ production were unknown. After Poly (I:C)stimulation, keratinocytes rapidly produced IFN-β, but IFN-κinstead was only produced after a prolonged time delay. BlockingIFNAR only resulted in inhibiting IFN-κ. Similarly, inhibition ofIFN-β decreased IFN-κ production. IFN-β knockout cell lineswere incapable of producing IFN-κ after either Poly I:C or UVBstimulation. These results altogether demonstrate that IFN-κ isboth an IFN gene and an IFN-simulated gene.Frontiers in Lupus 02The work of Xia et al. assesses the effect of losing amechanism of chemokine degradation in a model of lupusnephritis. The atypical chemokine receptor 2 (ACKR2) is foundin the afferent lymphatics of many human tissues and can bindmost of the CC chemokines. Through the expression of ACKRs,lymphatic vessels regulate chemokine levels and immune cellmigration. The researchers used blood and tissues fromACKR2-deficient lupus-prone B6lpr and WTB6lpr mice todetermine alterations to cellular patterns of inflammation andorgan damage. In B6lpr mice that developed lupus nephritis,ACKR2 deficiency resulted in greater T and B celltubulointerstitial inflammation, but these alterations were notassociated with greater renal disease or higher levels ofthe assessed inflammatory mediators. These results show thatthe loss of ACKR2-mediated chemokine degradation can becompensated in vivo by other mechanisms.The combined work of all these papers demonstrates the valueof intracellular signaling events to in vivo mechanisms furthershedding light on the complexity of SLE.Author contributionsWW: Writing – original draft, Writing – review & editing. JR:Writing – original draft, Writing – review & editing. AP: Writing –original draft, Writing – review & editing.Conflict of interestWW is employed by AstraZeneca and owns stock inAstraZeneca.The remaining authors declare that the research was conductedin the absence of any commercial or financial relationships thatcould be construed as a potential conflict of interest.Publisher’s noteAll claims expressed in this article are solely those of theauthors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and thereviewers. Any product that may be evaluated in this article, orclaim that may be made by its manufacturer, is not guaranteedor endorsed by the publisher.frontiersin.org

Editorial: New insights into interferons and proinflammatory cytokines in lupus

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Editorial: New insights into interferons and proinflammatory cytokines in lupus

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