Singh, S.; Ahmed, F.; Fatima, N.; Cholleti Sai, N.; Bhuktar, H.; Khan, R. A.; Afroz, S.; Battu, S.; Reddy, K. K.; Jagadeb, M.; Naz, S.; Sharma, N.; Philips, A. M.; Priscilla, T.; Vindal, V.; Kumar, M. J. M.; Oruganti, S.; Pal, M.; Reddanna, P.; Khan, N.

Inflammation plays a pivotal role in the etiopathogenesis of chronic inflammatory skin diseases. However, the underlying mechanism remains unclear. Here, we employed Gene expression meta-analysis and clinical validation to dissect the global architecture of immune dysregulation responsible for inflammatory conditions in the skin. Using such approaches, we identified a gene signature comprising of ALOX12B, which is significantly upregulated in psoriatic and atopic dermatitis patient skin samples, and correlates with increased levels of pathological IL-1{beta} and Th17 responses. Surprisingly, ALOX12B is predominantly expressed in the skin. Furthermore, skin-specific overexpression of human ALOX12B in transgenic mice resulted in psoriasis-like inflammatory symptoms, including epidermal hyperplasia, immune cell infiltration, and elevated IL-1{beta}/Th17 responses. ALOX12B is a non-heme iron-containing enzyme that catalyses the production of 12R-HETE from polyunsaturated fatty acids such as arachidonic acid. Mechanistically, we found that ALOX12B/12R-HETE accumulation in the skin acts as an intrinsic danger signal that triggers enhanced IL-1{beta} processing and secretion via ROS generation and NLRP3 inflammasome activation. Increased IL-1{beta} levels in turn drive IL-17 producing T-cell polarization. We further designed a novel first-in-class, potent, ALOX12B inhibitor, 6a, which exhibited favorable topical pharmacokinetic and safety profiles. The topical application of 6a reduced inflammation-associated pathologies in Tg-hALOX12B mice by suppressing 12R-HETE-induced IL-1{beta} production and ROS generation. These findings revealed a novel mechanism mediated by ALOX12B/12R-HETE overexpression that controls skin inflammation, thereby providing a promising therapeutic target for treating inflammatory skin diseases.