The Actin Cytoskeleton Responds to Inflammatory Cues and Alters Macrophage Activation

Abstract

Much remains to be learned about the molecular mechanisms underlying a class of human disorders called actinopathies. These genetic disorders are characterized by loss-of-function mutations in actin-associated proteins that affect immune cells, leading to human immunopathology. However, much remains to be learned about how cytoskeletal dysregulation promotes immunological dysfunction. The current study reveals that the macrophage actin cytoskeleton responds to LPS/IFNγ stimulation in a biphasic manner that involves cellular contraction followed by cellular spreading. Myosin II inhibition by blebbistatin blocks the initial contraction phase and lowers iNOS protein levels and nitric oxide secretion. Conversely, conditional deletion of Arp2/3 complex in macrophages attenuates spreading and increases nitric oxide secretion. However, iNOS transcription is not altered by loss of myosin II or Arp2/3 function, suggesting post-transcriptional regulation of iNOS by the cytoskeleton. Consistent with this idea, proteasome inhibition reverses the effects of blebbistatin and rescues iNOS protein levels. Arp2/3-deficient macrophages demonstrate two additional phenotypes: defective MHCII surface localization, and depressed secretion of the T cell chemokine CCL22. These data suggest that interplay between myosin II and Arp2/3 influences macrophage activity, and potentially impacts adaptive-innate immune coordination. Disrupting this balance could have detrimental impacts, particularly in the context of Arp2/3-associated actinopathies.

The release of osteoclast-stimulating factors on supraphysiological loading by osteoprogenitors coincides with expression of genes associated with inflammation and cytoskeletal arrangement

“…Inflammatory markers have also been reported to affect cytoskeletal rearrangement in many cell types. In macrophages, inflammatory activation by either lipopolysaccharide (LPS) and interferon gamma (IFNγ) results in a biphasic response where dynamic reorganization of actin and myosin initiates a contractile phase followed by a later spreading phase 53 . In addition, the activation of the complement system has shown to directly interact with intermediate filaments in monocytes, leading to their degredation 54 and a disruption of the cellular membrane 55 .…”

MRTF May Be the Missing Link in a Multiscale Mechanobiology Approach toward Macrophage Dysfunction in Space

“…Mφ pro-inflammatory activation and cytoskeletal reorganization occurs in a biphasic manner (Jain and Vogel, 2018;Ronzier et al, 2022): firstly in a chemical and secondly a mechanotransductive phase lasting 0-3 hours and 3-24 hours respectively. In the first stage, activation of surface receptors induces NF-κB/p65 nuclear translocation.…”

“…Created with BioRender.com. * (Bian et al, 2017;Mu, 2018;Ronzier et al, 2022), †(Jiménez-Garcia et al, 2015, ‡(C. , § (Miranda et al, 2021).…”

MRTF may be the missing link in a multiscale mechanobiology approach toward macrophage dysfunction in space

“…Mϕ pro-inflammatory activation and cytoskeletal reorganization occurs in a biphasic manner ( Jain and Vogel, 2018 ; Ronzier et al, 2022 ): firstly in a chemical and secondly a mechanotransductive phase lasting 0–3 h and 3–24 h, respectively. In the first stage, activation of surface receptors induces NF-κB/p65 nuclear translocation.…”

“…Created with BioRender.com . *( Bian et al, 2017 ; Mu, 2018 ; Ronzier et al, 2022 ). ‡( Wang C. et al, 2015 ).…”