Session Title: Systemic Lupus Erythematosus – Animal Models - Poster I
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: Skin inflammation appears in cutaneous or systemic lupus erythematosus. Ultraviolet B (UVB) is an important environmental trigger of skin inflammation in lupus. Mechanisms linking UVB to autoimmune inflammation in lupus are not well understood. Neutrophils, the most abundant circulating leukocytes, are the first group of cells to be recruited to the site of photodamage, prior to monocytes and lymphocytes, in response to UVB-irradiation. Studies have suggested that neutrophils may pave the way for the subsequent recruitment of monocytes and lymphocytes. All of these cell types orchestrate and together contribute to the local inflammation at the site of photodamage, and the systemic consequences. However, little is known about the role of 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 pathogenesis. NETs develop as release of the decondensed nuclear chromatin from a ruptured nuclear envelope. Recent studies from our and other groups indicate the importance of the actin cytoskeleton in neutrophil NETosis. Rho kinase (ROCK) is known to regulate actin-myosin (actomyosin) networks. Whether ROCK regulates neutrophil NETosis and contributes to UVB-induced skin inflammation has not been investigated.
Methods: To explore the role of ROCK in neutrophil NETosis, we investigated the effects of ROCK inhibition on neutrophil NETosis in vitro in human neutrophils and neutrophil NETosis in UVB-induced skin inflammation in mice.
Results: In vitro, we found that PMA stimulation induced F-actin polymerization and ROCK activation in human neutrophils. In addition, inhibition of ROCK activation attenuated F-actin polymerization. Importantly, inhibition of ROCK by different ROCK inhibitors, or interfering F-actin polymerization with cytochalasin D, significantly alleviated PMA-induced NET formation in human neutrophils. To explore the effects of ROCK in vivo in UVB-induced skin inflammation, we found that exposure of female C57BL/6J WT mice to UVB with a dose of 250 mJ/cm2/day for 5 consecutive days induces neutrophil recruitment and NET formation which display IL-17 in the dermis of mouse skin. Importantly, application of the dual ROCK1/2 inhibitor HA1077 intraperitoneally (i.p.) attenuated neutrophil recruitment and NET formation in UVB-irradiated mouse skin in vivo. Most importantly, ROCK inhibition attenuated neutrophil NETosis among the infiltrated neutrophils in the UVB-exposed mouse skin.
Conclusion: Our preliminary studies therefore elucidated a novel mechanism that ROCK regulates neutrophil NET release, and confirmed the protective role of ROCK inhibition in neutrophil NETosis both in vitro and in vivo. Our findings may provide insights into a novel therapeutic target for treatment of UVB-induced skin inflammation, including lupus.
To cite this abstract in AMA style:Liu ML, Sharma M, Werth VP. Novel Role of Rho Kinase in Neutrophil Netosis during UVB Induced-Skin Inflammation [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/novel-role-of-rho-kinase-in-neutrophil-netosis-during-uvb-induced-skin-inflammation/. Accessed October 22, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/novel-role-of-rho-kinase-in-neutrophil-netosis-during-uvb-induced-skin-inflammation/