
Scripps Research discovery suggests new strategy against harmful inflammation Scientists identify WASH protein complex as a gatekeeper of neutrophil-driven inflammation
September 21, 2022
LA JOLLA, CA A team led by Scripps Research scientists has uncovered key details of an immune-cell process that frequently underlies excessive inflammation in the body. The findings could lead to new ways of preventing and/or treating inflammation-related conditions such as sepsis, arthritis, and coronary artery disease.
In the study, published September 21, 2022 in Nature Communications, the researchers showed that a multi-protein molecular machine called WASH has a powerful role in restraining excessive inflammatory activity by neutrophils, immune cells that are important early responders against infections.
Our findings point to the possibility of future treatments that target this WASH-regulated pathway to inhibit neutrophil-driven inflammation while preserving most of neutrophils' anti-microbial effectiveness, says study senior author Sergio Catz, PhD, professor in the Department of Molecular Medicine at Scripps Research.
Neutrophils are workhorses of the mammalian immune system, comprising about two-thirds of the white blood cells that circulate through our bloodstreams. They combat invading microbes by engulfing and digesting them, and by releasing a variety of antimicrobial molecules via a process called exocytosis.
Many of the antimicrobial molecules that neutrophils release via exocytosis are potent enough to harm healthy cells. There is evidence that excessive and/or chronic release of these molecules at least partly underlies serious medical conditions and types of tissue injury, including the bacterial blood-infection condition known as sepsis, arthritis, reperfusion injury to cells after oxygen deprivation, smoke inhalation injury to lungs, inflammatory bowel disease, some cancers, and even the artery-thickening atherosclerosis that leads to heart attacks and strokes. Yet scientists still have a lot to learn about how this exocytosis process works.
In the new study, Catz and his team illuminated the important role WASH plays in neutrophil exocytosis. Neutrophils, when they encounter signs of infection or inflammation, typically respond initially by releasing, via exocytosis, milder compounds within gelatinase granules capsule-like enclosures named for one of the enzymes found within them. A second type of exocytosis, triggered secondarily and usually only by more severe infection or inflammation, involves the release of azurophilic granules, so-called because they are bound by a common blue stain. Azurophilic cargoes are far more potent and are more likely to damage bystander cells. The team showed that WASH normally facilitates the initial gelatinase granule response, which includes the release of compounds that help neutrophils adhere to and move around surfaces such as blood vessel walls. At the same time, WASH normally restrains the release of toxic azurophilic granules cargoes.
In experiments, neutrophils without WASH released excessive amounts of azurophilic granules. Mice with these neutrophils had blood levels of toxic azurophilic molecules that are normally found in cases of harmful systemic inflammation. The mortality rate of such mice when experiencing an experimental sepsis-like condition was more than triple that of normal mice.
WASH seems to be an important molecular switch that controls neutrophils' responses to infection and inflammation by regulating the release of these two kinds of antimicrobial cargoes, Catz says. When WASH is dysfunctional, the result is likely to be excessive and chronic inflammation.
In this study, using state-of-the-art cell biology approaches, we reveled how neutrophils control their timely response through sequential exocytosis, and have identified a molecular system that acts as the gatekeeper of this process, Catz adds.
Catz and his colleagues are continuing to study WASH and other molecules involved in neutrophil exocytosis, with the goal of finding candidate drug molecules that can damp excessive azurophilic granule exocytosis to treat inflammatory conditions without impairing neutrophils' functions as immune first responders.
The study's co-first authors were Senior Staff Scientist Jennifer Johnson, PhD, and postdoctoral researchers Elsa Meneses-Salas PhD, and Mahalakshmi Ramadass, PhD, all members of the Catz lab during the study.
Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation was co-authored by Jennifer Johnson, Elsa Meneses-Salas, Mahalakshmi Ramadass, Jlenia Monfregola, Farhana Rahman, Raquel Carvalho Gontijo, Kersi Pestonjamasp, Dale Allen, Jinzhong Zhang, Kasra Askari, Danni Chen, Juan Yu, Scott Henderson, Nathan Wineinger and Sergio Catz, from Scripps Research; William Kiosses, Yanfang Peipei Zhu and Catherine Hedrick from the La Jolla Institute for Immunology; Douglas Osborne and Daniel Billadeau from the Mayo Clinic; Matilde Valeria Ursini of the Italian National Research Council's Institute of Genetics and Biophysics A. Buzzati Traverso; and Sergio Grinstein of the University of Toronto.
The research was funded in part by the National Institutes of Health (P01HL152958, R01HL088256, R01AR070837, R01DK110162).
Molecular and Cellular Biology Catz, Sergio
Most recent headlines
06/10/2025
France T l visions, France's leading broadcaster, has received the 2025 EBU ...
06/09/2025
(L-R) Dylan O'Brien and James Sweeney attend the 2025 Sundance Film Festival Twinless premiere at Eccles Theatre. (Photo by George Pimentel/Shutterstock f...
06/09/2025
LONDON Vizrt has introduced Viz Arena 6, the newest version of its all-in-one live augmented reality (AR) graphics and virtual advertising sports solution. The ...
06/09/2025
SEATTLE Amazon Web Services (AWS) will feature 56 AWS Partners making various demos that showcase the technologies and use cases shaping the future of the Media...
06/09/2025
In news that highlights the ongoing importance of video games, PBS Kids is making its first foray into gameplay content with the September 5 launch of Odd Squa...
06/09/2025
PBS chief executive Paula Kerger has sent an email to staff outlining plans to cut about 100 positions or 15% of its staff, following the loss of Federal fundin...
06/09/2025
A new era of recognition as IABM honors the people, projects and innovations driving real impact
IABM has confirmed the shortlist for the new IABM Impact Award...
06/09/2025
Vizrt, the leader in live production technology revolutionizing viewer experiences, announces new capabilities to help customers create once, adapt automaticall...
06/09/2025
Studio Technologies, a leading manufacturer of high-quality audio, video, and fiber-optic solutions, will spotlight four of its innovative audio solutions at th...
06/09/2025
DigitalGlue, creator of the award-winning creative.space managed storage platform, today announced a technology preview of Creative Intelligence (CI) powered by...
06/09/2025
Eye Filmmuseum is the Netherlands leading film museum, offering a rich variety of experiences from screenings of classic films to cultural exhibitions. With fou...
06/09/2025
The latest innovations in Grass Valley's AMPP applications will be on full display at IBC 2025, as the company brings significant updates to Playout X, its ...
06/09/2025
Disguise has announced the launch of the GX 3 , its most powerful media server ever. Built on NVIDIA's cutting-edge Blackwell GPU architecture and including...
06/09/2025
Autoscript and Autocue have announced the launch of a new advanced PTZ prompter system shared by both brands and designed to provide seamless, professional prom...
06/09/2025
Sachtler has added four new models to its award-winning aktiv and FSB Mk II fluid head ranges. The aktiv16T and aktiv18T, plus the FSB 16T Mk II and FSB 18T Mk...
06/09/2025
CGI (TSX: GIB.A) (NYSE: GIB), one of the largest independent IT and business consulting services firms in the world, will present its bold new vision for the fu...
06/09/2025
DHD has chosen IBC 2025 (Amsterdam, 12-15 September) as the launch venue for the latest version of its RM1 all-in-one portable audio production and broadcast sy...
06/09/2025
AJA Video Systems debuted IP25-R, a Mini-Converter for connecting SMPTE ST 2110 networks with 4K SDI/HDMI infrastructures. IP25-R lets broadcast, production, an...
06/09/2025
AJA Video Systems today introduced new products and updates ahead of the International Broadcasting Convention (IBC) 2025 that streamline signal flow management...
06/09/2025
Researchers map key human proteins that power coronavirus replication, pointing to new treatment strategies Findings from Scripps Research reveal promising drug...
05/09/2025
Your listening habits are as unique as you are-and this year, Spotify has introduced a wave of new features to help you personalize your experience. From playli...
05/09/2025
SBS kicks off a confident slate with the 2026 FIFA World Cup 2026 , premium dram...
05/09/2025
Today's Historic Settlement Underscores SBS's Powerful New Series The Pe...
05/09/2025
L3Harris Chief Financial Officer and Aerojet Rocketdyne President Ken Bedingfiel...
05/09/2025
PHILADELPHIA NBC Sports will present tonight's NFL Kickoff Game between the '25 Super Bowl champion Philadelphia Eagles and Dallas Cowboys on Peacock in...
05/09/2025
Warner Bros. Discovery filed a lawsuit against Gen AI company Midjourney this week, claiming that the company violated the studio's copyright....
05/09/2025
Alum Esin Ayd ng z Pens Nevermore Alma Mater' for Netflix's Wednesday The Grammy-nominated composer appears on this season's soundtrack alongside...
05/09/2025
C-SPAN and YouTube this week announced an agreement in which YouTube will sponsor C-SPAN's America 250 programming and expand access to C-SPAN's politic...
05/09/2025
LONDON Live broadcast infrastructure solutions provider Techex has added Peter Dawidzik as senior director, sales and business development....
05/09/2025
As news organizations and broadcasters face more pressure than ever to capture, verify, and distribute real-time access to breaking news, Reuters and Amazon Web...
05/09/2025
LOS ANGELES The Hollywood Professional Association (HPA) today said it has begun accepting submissions for its expanded HPA Engineering Excellence Awards, which...
05/09/2025
Sage has released an update to its most recent firmware for its Digital ENDEC model 3644....
05/09/2025
LONDON and LOS ANGELES ThinkAnalytics will debut ThinkMetadataAI, the company's latest step in recommendations, search and discovery services....
05/09/2025
WASHINGTON The Federal Communications Commissions Media Bureau has announced that the agency is initiating a phased process to lift the current freeze on major ...
05/09/2025
TORONTO Quickplay will feature its newly unveiled AI Studio that assists broadcasters and streamers in transforming their content libraries into short-form asse...
05/09/2025
Boston Conservatory at Berklee Announces Five-Year Partnership with The Verdon F...
05/09/2025
Alum Esin Ayding z Pens Nevermore Alma Mater' for Netflix's Wednesday The Grammy-nominated composer appears on this season's soundtrack alongside...
05/09/2025
Rohde & Schwarz UK awarded Silver Award under Defence Employer Recognition Schem...
05/09/2025
Back to All News
Two Desperate Souls and One Desperate Choice: As You Stood By...
05/09/2025
Back to All News
Netflix Unveils New BAKI-DOU' Anime and First Look at BE...
05/09/2025
This weekend sees another feast in store for all sport fans as RT airs a jam-packed schedule of live, free-to-air sport.
The Amgen Irish Open continues all we...
04/09/2025
(Joel Edgerton and Felicity Jones appear in Train Dreams by Clint Bentley, an of...
04/09/2025
SBS kicks off a confident slate with the 2026 FIFA World Cup2026 , premium drama...
04/09/2025
Watch the Record-breaking Koori Knockout 2025 LIVE and EXCLUSIVE on NITV and SBS...
04/09/2025
WALTHAM, Mass. Zixi, a provider of video-delivery-over-IP technology, has named Sue Mitchell as director of account management, EMEA....
04/09/2025
NEW YORK In news that highlights the importance of the NFL and sports for the TV and streaming industry, NBCUniversal is reporting record revenue for its 20th s...
04/09/2025
OTTAWA Ross Video has acquired LAMA, a Dutch-based developer of advanced audio production software known for its innovative live mixing solutions. The acquisiti...
04/09/2025
CINCINNATI GatesAir will bring its 5G passthrough demo to IBC audiences once again as interest in the technology's value for broadcast-to-mobile delivery gr...
04/09/2025
BURY ST. EDMUNDS, England Autoscript and Autocue will showcase their newly launched PTZ prompter system during IBC2025, Sept. 12-15 at the RAI Amsterdam Convent...
04/09/2025
Watch the Benn Family Band Perform I Wont Give Up on Americas Got Talent Assistant Professor Loren Benn and her family gave an emotional live performance of t...