Rock-Mediated Pkca Nuclear Translocation Is Important in Neutrophil Netosis and UVB Induced-Skin Inflammation

Ming-Lin Liu¹, Yubin Li², Meena Sharma³ and Victoria P. Werth⁴, ¹Department of Dermatology,, Philadelphia V.A. Medical Center, Philadelphia, PA, ²Dermatology, University of pennsylvania, Philadelphia, PA, ³Department of Dermatology, Philadelphia V.A. Medical Center, Philadelphia, PA, ⁴Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA

Meeting: 2017 ACR/ARHP Annual Meeting

Date of first publication: September 18, 2017

Keywords: Neutrophil Extracellular Traps

Session Information

Date: Tuesday, November 7, 2017

Title: Systemic Lupus Erythematosus – Animal Models Poster

Session Type: ACR Poster Session C

Session Time: 9:00AM-11:00AM

Background/Purpose:

Neutrophils are the most abundant circulating leukocytes and the earliest inflammatory cells to be recruited to the site of photodamage after ultraviolet B (UVB) exposure. However, little is known about the role of the neutrophils in UVB-induced skin inflammation. Neutrophil NETosis is a newly characterized neutrophil cell death that releases neutrophil extracellular traps (NETs), which have been shown to be important in autoimmune inflammation, including lupus. Recent studies from our and other groups indicate the importance of actin cytoskeleton in neutrophil NETosis. Since actin-myosin cytoskeleton is known to be regulated by Rho kinase (ROCK), our recent studies have demonstrated the role of ROCK in PMA-induced neutrophil NETosis in vitro and NETotic neutrophils in UVB-induced skin inflammation in vivo. However it not clear how ROCK and its regulated cytoskeleton is involved in neutrophil NETosis.

Methods:

To explore the effects of ROCK on neutrophil NETosis, we investigated the effects of ROCK inhibition on neutrophil NETosis in vitro in human neutrophils and UVB-induced neutrophil NETosis in the inflamed skin in mice.

Results:

Following PMA stimulation, cytosolic PKCa is gradually translocated to the nuclear membrane. In particular, activated PKCa (phosphor-PKCa at ser657) accumulated at the site of nuclear membrane rupture in the NETotic neutrophils in our confocal analysis. Inhibition of actin, myosin, or MLCK (myosin light chain kinase) of actomyosin networks with cytochalasin D, Blebbistatin, or ML7 can attenuate nuclear translocation of PKCa and neutrophil NETosis. Similarly, the dual ROCK1/2 inhibitor HA1077 attenuated nuclear translocation of PKCa and PMA-induced NETosis. In addition, application of HA1077 intraperitoneally (i.p.) can also reduce UVB-exposure-induced NETosis among the infiltrated neutrophils in the inflamed skin.

Conclusion:

Our preliminary studies therefore elucidated a novel mechanism that ROCK-mediated nuclear translocation of PKCa regulates neutrophil NET formation, and confirmed the protective role of ROCK inhibition in neutrophil NETosis in vitro and in vivo. Our findings may provide insights into a novel therapeutic target for treatment of UVB-induced skin inflammation.

Disclosure: M. L. Liu, None; Y. Li, None; M. Sharma, None; V. P. Werth, None.

To cite this abstract in AMA style:

Liu ML, Li Y, Sharma M, Werth VP. Rock-Mediated Pkca Nuclear Translocation Is Important in Neutrophil Netosis and UVB Induced-Skin Inflammation [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/rock-mediated-pkca-nuclear-translocation-is-important-in-neutrophil-netosis-and-uvb-induced-skin-inflammation/. Accessed .

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