About: Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating

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About: Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
title	Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating
Creator	Buckles, Thomas Djukovic, Danijel Ziemba, Brian Falke Id, Joseph
source	Medline; PMC
abstract	Leukocyte migration is controlled by a membrane-based chemosensory pathway on the leading edge pseudopod that guides cell movement up attractant gradients during the innate immune and inflammatory responses. This study employed single cell and population imaging to investigate drug-induced perturbations of leading edge pseudopod morphology in cultured, polarized RAW macrophages. The drugs tested included representative therapeutics (acetylsalicylic acid, diclofenac, ibuprofen, acetaminophen) as well as control drugs (PDGF, Gö6976, wortmannin). Notably, slow addition of any of the four therapeutics to cultured macrophages, mimicking the slowly increasing plasma concentration reported for standard oral dosage in patients, yielded no detectable change in pseudopod morphology. This finding is consistent with the well established clinical safety of these drugs. However, rapid drug addition to cultured macrophages revealed four distinct classes of effects on the leading edge pseudopod: (i) non-perturbing drug exposures yielded no detectable change in pseudopod morphology (acetylsalicylic acid, diclofenac); (ii) adaptive exposures yielded temporary collapse of the extended pseudopod and its signature PI(3,4,5)P(3) lipid signal followed by slow recovery of extended pseudopod morphology (ibuprofen, acetaminophen); (iii) disruptive exposures yielded long-term pseudopod collapse (Gö6976, wortmannin); and (iv) activating exposures yielded pseudopod expansion (PDGF). The novel observation of adaptive exposures leads us to hypothesize that rapid addition of an adaptive drug overwhelms an intrinsic or extrinsic adaptation system yielding temporary collapse followed by adaptive recovery, while slow addition enables gradual adaptation to counteract the drug perturbation in real time. Overall, the results illustrate an approach that may help identify therapeutic drugs that temporarily inhibit the leading edge pseudopod during extreme inflammation events, and toxic drugs that yield long term inhibition of the pseudopod with negative consequences for innate immunity. Future studies are needed to elucidate the mechanisms of drug-induced pseudopod collapse, as well as the mechanisms of adaptation and recovery following some inhibitory drug exposures.
has issue date	2020-05-29(xsd:dateTime)
bibo:doi	10.1371/journal.pone.0233012
bibo:pmid	32469878
has license	cc-by
sha1sum (hex)	da93732bae58cd4d177dab387dc3804b1eaf4e56
schema:url	https://doi.org/10.1371/journal.pone.0233012
resource representing a document's title	Rapid exposure of macrophages to drugs resolves four classes of effects on the leading edge sensory pseudopod: Non-perturbing, adaptive, disruptive, and activating
has PubMed Central identifier	PMC7259666
has PubMed identifier	32469878
schema:publication	PLoS One
resource representing a document's body	covid:da93732bae58cd4d177dab387dc3804b1eaf4e56#body_text
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