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

摘要: Leukocyte migration is controlled by a membrane-based chemosensory pathway on the leading edge pseudopod that guides cell movement up attractant gradients during innate immune and inflammatory responses. This study employed single population imaging to investigate drug-induced perturbations of morphology in cultured, polarized RAW macrophages. The drugs tested included representative therapeutics (acetylsalicylic acid, diclofenac, ibuprofen, acetaminophen) as well control (PDGF, Go6976, wortmannin). Notably, slow addition any four cultured macrophages, mimicking slowly increasing plasma concentration reported for standard oral dosage patients, yielded no detectable change morphology. finding consistent with established clinical safety these drugs. However, rapid drug macrophages revealed distinct classes effects pseudopod: (i) non-perturbing exposures diclofenac); (ii) adaptive temporary collapse extended its signature PI(3,4,5)P3 lipid signal followed recovery (ibuprofen, acetaminophen); (iii) disruptive long-term (Go6976, wortmannin); (iv) activating expansion (PDGF). novel observation leads us hypothesize an overwhelms intrinsic or extrinsic adaptation system yielding recovery, while enables gradual counteract perturbation real time. Overall, results illustrate approach may help identify therapeutic temporarily inhibit extreme inflammation events, toxic yield long term inhibition negative consequences immunity. Future studies are needed elucidate mechanisms collapse, following some inhibitory exposures.