A novel target for neutrophil NETosis in lupus skin inflammation
Lupus patients develop skin rashes in response to sunlight and other triggers. Immune cells called neutrophils promote these lesions by spewing out their DNA. Dr. Liu has discovered that a protein known as ROCK is crucial to this process. He and his team will now test whether blocking ROCK stops neutrophils from releasing their DNA, thereby reducing skin inflammation in mice that are prone to lupus. the results of their study could suggest new ways to reduce skin rashes in lupus patients.
What this study means for people with lupus
Skin rashes are common in lupus patients. Dr. Liu’s research will ask whether preventing certain immune cells from releasing their DNA curbs skin inflammation.
Autoimmune skin inflammation is common in both systemic and cutaneous lupus erythematosus (SLE, CLE), and characterized by accumulation of antibodies, immune cells, and cytokines in skin lesions. Neutrophils are the most abundant circulating leukocytes. UVB is an important trigger of skin rashes in lupus, and recruits neutrophils, monocytes and lymphocytes to the site of photodamage. NETosis is a novel type of neutrophil cell death and releases neutrophil extracellular traps (NETs). NETs have been detected in the skin lesions of SLE patients. NETs contain autoantigens, display IL-17, and crosstalk with pDCs to release type I interferons (IFN), thus sustain autoimmune responses in lupus. Little is known about the role of neutrophils in UVB-induced skin inflammation. NETs develop as release of decondensed nuclear DNA via a ruptured nuclear envelope (NuEn). Degradation of nuclear lamina is required for NuEn breakdown during mitosis, apoptosis, and viral infection in which lamin B is degraded by PKC. Mature primary and HL-60 neutrophils have lamin B associated with the NuEn, but lack lamin A/C. Therefore degradation of lamin B is required for NuEn rupture and NET release. We revealed a novel mechanism that ROCK-mediated nuclear translocation of PKCa which serve as NETotic nuclear lamin kinase to degrade lamin B and breakdown NuEn, thus results in DNA release and NET formation. We also established an animal model of UVB-induced skin inflammation with neutrophil NETosis in wildtype mice. Inhibition of ROCK by HA-1077 attenuated NET release and the display of IL-17 in the mouse skin. We therefore hypothesized that ROCK-mediated PKCa nuclear translocation regulates neutrophil NETosis and contributes to skin inflammation in lupus. In Aim 1, we will examine the effects of ROCK inhibition on neutrophil NETosis and skin inflammation in UVB-induced skin lupus in MRL/lpr mice. We will also evaluate the involvement of ROCK isoforms and protective role of ROCK inhibitors in skin inflammation in these mice. In Aim 2, we will determine the role ROCK-mediated PKCa nuclear translocation in NETosis in NDG and LDG neutrophils from lupus patients. We will examine ROCK activities, PKCa nuclear translocation, and spontaneous NETosis in NDG and LDG neutrophils isolated from patients with CLE or SLE. The effects of ROCK (HA-1077-dual ROCK1/2, or KD025-selective ROCK2) inhibitors on neutrophil NETosis in lupus patients will be studied. We will also detect NET components, IL-17, and IFNa in skin lesions and in blood of these subjects, and then analyze their associations with severity of skin lesion (CLASI score) in lupus patients. The study will target on neutrophils and identify a novel role of ROCK-mediated PKCa nuclear translocation in neutrophil NETosis and autoimmune skin inflammation in lupus. Completion of the study will extend our understanding regarding the role of ROCK pathway in lupus pathogenesis and provide insight for new treatment of lupus skin inflammation.