IRF5 distinguishes severe asthma in humans and drives Th1 phenotype and airway hyperreactivity in mice

JCI Insight
Timothy B OrissAnuradha Ray

Abstract

Severe asthma (SA) is a significant problem both clinically and economically, given its poor response to corticosteroids (CS). We recently reported a complex type 1-dominated (IFN-γ-dominated) immune response in more than 50% of severe asthmatics despite high-dose CS treatment. Also, IFN-γ was found to be critical for increased airway hyperreactivity (AHR) in our model of SA. The transcription factor IRF5 expressed in M1 macrophages can induce a Th1/Th17 response in cocultured human T cells. Here we show markedly higher expression of IRF5 in bronchoalveolar lavage (BAL) cells of severe asthmatics as compared with that in cells from milder asthmatics or healthy controls. Using our SA mouse model, we demonstrate that lack of IRF5 in lymph node migratory DCs severely limits their ability to stimulate the generation of IFN-γ- and IL-17-producing CD4+ T cells and IRF5-/- mice subjected to the SA model displayed significantly lower IFN-γ and IL-17 responses, albeit showing a reciprocal increase in Th2 response. However, the absence of IRF5 rendered the mice responsive to CS with suppression of the heightened Th2 response. These data support the notion that IRF5 inhibition in combination with CS may be a viable approach to manage dise...Continue Reading

References

Jul 1, 1990·American Journal of Respiratory Cell and Molecular Biology·E K Tam, G H Caughey
Jan 1, 1988·The Journal of Experimental Medicine·C M SnapperW E Paul
Apr 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·J PunnonenJ E de Vries
Feb 1, 1997·The Journal of Allergy and Clinical Immunology·L Borish, L Rosenwasser
Dec 6, 2000·The Journal of Experimental Medicine·Z WangJ A Elias
Jan 4, 2001·The Journal of Experimental Medicine·K Y VermaelenR A Pauwels
Aug 9, 2003·Biochemical Pharmacology·Victor E BarriosClifford D Wright
Oct 4, 2003·Journal of Leukocyte Biology·Kate SchroderDavid A Hume
Jul 3, 2004·The Journal of Clinical Investigation·Marina OstroukhovaAnuradha Ray
Jan 7, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Timothy B OrissAnuradha Ray
Oct 21, 2005·Proceedings of the National Academy of Sciences of the United States of America·Hideo NegishiKenya Honda
Sep 20, 2006·The Journal of Immunology : Official Journal of the American Association of Immunologists·Euan LockhartJoAnne L Flynn
Dec 26, 2006·Vaccine·Thomas EbensenCarlos A Guzmán
Apr 11, 2008·Immunity·Mandy J McGeachy, Daniel J Cua
Apr 26, 2008·Proceedings of the National Academy of Sciences of the United States of America·Hui XuAnuradha Ray
Jul 22, 2009·The Journal of Immunology : Official Journal of the American Association of Immunologists·Alun C KirbyPaul M Kaye
Sep 4, 2010·American Journal of Respiratory and Critical Care Medicine·Silvana BalzarSally E Wenzel
Jan 8, 2011·The Journal of Allergy and Clinical Immunology·Sarah Beth L Barnett, Tursynbek A Nurmagambetov
Jan 18, 2011·Nature Immunology·Thomas KrausgruberIrina A Udalova
Mar 16, 2011·Proceedings of the National Academy of Sciences of the United States of America·Mingjian FeiAnuradha Ray
Aug 2, 2011·Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology·Stanley J SzeflerBradley E Chipps
Sep 29, 2011·Nature·Dara L BurdetteRussell E Vance
Nov 22, 2011·Sleep & Breathing = Schlaf & Atmung·Faith S LuysterSally E Wenzel
Mar 14, 2012·The Journal of Allergy and Clinical Immunology·Lara J AkinbamiRobert A Smith
Mar 10, 2012·Nature Reviews. Immunology·Thomas J BracialeTaeg S Kim
Mar 21, 2012·Proceedings of the National Academy of Sciences of the United States of America·Whitney E PurthaDeepta Bhattacharya

❮ Previous
Next ❯

Citations

Mar 25, 2018·Scientific Reports·Christina DraijerBarbro N Melgert
Jul 10, 2018·International Reviews of Immunology·Ashwinder KaurChee-Mun Fang
Jul 15, 2018·Reproduction : the Official Journal of the Society for the Study of Fertility·Ratana LimMartha Lappas
Oct 26, 2018·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·Dasom KimIan P Lewkowich
Feb 23, 2019·Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology·Alberta G A PaulJudith A Woodfolk
Jan 10, 2020·Physiological Reviews·Anuradha RaySally E Wenzel
Jul 22, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Jie YanClara Abraham
Dec 6, 2018·Frontiers in Immunology·Cherrie D ThompsonBetsy J Barnes
Sep 10, 2020·American Journal of Physiology. Lung Cellular and Molecular Physiology·Maya MikamiCharles W Emala
Aug 26, 2019·The Journal of Allergy and Clinical Immunology·William J BranchettClare M Lloyd
Jun 27, 2020·The European Respiratory Journal·Timothy S C HinksGuy G Brusselle
Jan 11, 2021·Clinical and Experimental Immunology·G J AlbersA J Byrne
Jan 22, 2021·Allergy, Asthma & Immunology Research·Hwa Young LeeSook Young Lee
Oct 27, 2017·Translational Research : the Journal of Laboratory and Clinical Medicine·Arjun SaradnaPeisong Gao
Mar 28, 2021·Current Opinion in Immunology·Matthew J CamioloAnuradha Ray
Oct 27, 2020·Frontiers in Immunology·Helen E RichMichelle L Manni
Jul 22, 2021·Experimental & Molecular Medicine·Quang Luu QuocHae-Sim Park
Jun 20, 2021·The Journal of Allergy and Clinical Immunology·Marc GauthierAnuradha Ray
Oct 1, 2021·JCI Insight·Matthew J CamioloSally E Wenzel
Nov 11, 2021·American Journal of Physiology. Lung Cellular and Molecular Physiology·Brandon W LewisRodney D Britt
Sep 12, 2020·Medicinal Chemistry·Renata Virgínia Cavalcanti SantosMoacyr Jesus Barreto de Melo Rêgo

❮ Previous
Next ❯

Methods Mentioned

BETA
bronchoalveolar
lavage
fluorescence-activated cell sorting
reverse transcription PCR
transfection
FCS
ELISA

Software Mentioned

FlowJo
GraphPad Prism
Tree Star

Related Concepts

Related Feeds

Asthma

This feed focuses in Asthma in which your airways narrow and swell. This can make breathing difficult and trigger coughing, wheezing and shortness of breath.

Allergy and Asthma

Allergy and asthma are inflammatory disorders that are triggered by the activation of an allergen-specific regulatory t cell. These t cells become activated when allergens are recognized by allergen-presenting cells. Here is the latest research on allergy and asthma.