Inhibiting nonmuscle myosin II impedes inflammatory infiltration and ameliorates progressive renal disease.
The motor protein nonmuscle myosin II (NMII) through its interaction with the actin cytoskeleton constitutes the machinery of cell crawling and has an important role in driving locomotion and infiltration of immune competent cells during inflammatory response and immune reaction. Blebbistatin is a highly selective inhibitor of NMII adenosine triphosphatase. This study examined the effect of NMII inhibition by blebbistatin on inflammation. In vitro, blebbistatin markedly induced actinomyosin complex disassembly in various cultured immunocytes, and functionally impaired their motile activity and invasive capacity as assessed by the Boyden chamber motility assay and the matrigel invasion assay. In vivo, in a rat model of acute inflammation induced by tumor necrosis factor, blebbistatin obliterated renal sequestration of circulating fluorescence-labeled macrophages in a dose-dependent fashion. Moreover, in rats with progressive obstructive nephropathy, blebbistatin treatment exhibited a remarkable renoprotective effect, as evidenced by normalized kidney weight, improved gross morphology, and diminished histologic injury in the tubulointerstitium. This beneficial effect was associated with significant amelioration of renal inflammation, consistent with a primary anti-inflammatory action by blebbistatin. In addition, in rats with established obstructive nephropathy, blebbistatin pretreated macrophages showed obliterated recruitment into the inflamed renal parenchyma, denoting that blebbistatin directly impedes inflammatory infiltration by immunocytes. Collectively, our findings suggest that inhibition of NMII has a potent and direct anti-inflammatory effect on the basis of impairment of the actinomyosin powered locomotive machinery, which is essential for migration and infiltration of immune competent cells.
Si
Jin
J
Department of Medicine, Brown University School of Medicine, Providence, RI, USA.
Ge
Yan
Y
Zhuang
Shougang
S
Gong
Rujun
R
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D019169:Jurkat Cells; D007668:Kidney / Q000473:pathology; D008264:Macrophages / Q000187:drug effects; D008297:Male; D009393:Nephritis / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology; D024507:Nonmuscle Myosin Type IIA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha; D014517:Ureteral Obstruction / Q000150:complications
D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; D014409:Tumor Necrosis Factor-alpha; C472645:blebbistatin; D024507:Nonmuscle Myosin Type IIA