@article {6681, title = {Extracellular Caspase-1 induces hair stem cell migration in wounded and inflamed skin conditions.}, journal = {J Cell Biol}, volume = {223}, year = {2024}, month = {2024 Jul 01}, abstract = {

The wound-healing process is a paradigm of the directed migration of various pools of stem cells from their niche to the site of injury where they replenish damaged cells. Two decades have elapsed since the observation that wounding activates multipotent hair follicle stem cells to infiltrate the epidermis, but the cues that coax these cells out of their niche remain unknown. Here, we report that Caspase-1, a protein classically known as an integral component of the cytosolic inflammasome, is secreted upon wounding and has a non-canonical role in the extracellular milieu. Through its caspase activation recruitment domain (CARD), Caspase-1 is sufficient to initiate the migration of hair follicle stem cells into the epidermis. Uncovering this novel function of Caspase-1 also facilitates a deeper understanding of the mechanistic basis of the epithelial hyperplasia found to accompany numerous inflammatory skin diseases.

}, keywords = {Animals, Caspase 1, Cell Movement, Dermatitis, Hair, Hair Follicle, Inflammation, Mice, Stem Cells, Wound Healing}, issn = {1540-8140}, doi = {10.1083/jcb.202306028}, author = {Hegde, Akshay and Ghosh, Subhasri and Ananthan, Akhil Shp and Kataria, Sunny and Dutta, Abhik and Prabhu, Srilekha and Khedkar, Sneha Uday and Dutta, Anupam and Jamora, Colin} } @article {6679, title = {Metabolic rewiring of macrophages by epidermal-derived lactate promotes sterile inflammation in the murine skin.}, journal = {EMBO J}, volume = {43}, year = {2024}, month = {2024 Apr}, pages = {1113-1134}, abstract = {

Dysregulated macrophage responses and changes in tissue metabolism are hallmarks of chronic inflammation in the skin. However, the metabolic cues that direct and support macrophage functions in the skin are poorly understood. Here, we show that during sterile skin inflammation, the epidermis and macrophages uniquely depend on glycolysis and the TCA cycle, respectively. This compartmentalisation is initiated by ROS-induced HIF-1α stabilization leading to enhanced glycolysis in the epidermis. The end-product of glycolysis, lactate, is then exported by epithelial cells and utilized by the dermal macrophages to induce their M2-like fates through NF-κB pathway activation. In addition, we show that psoriatic skin disorder is also driven by such lactate metabolite-mediated crosstalk between the epidermis and macrophages. Notably, small-molecule inhibitors of lactate transport in this setting attenuate sterile inflammation and psoriasis disease burden, and suppress M2-like fate acquisition in dermal macrophages. Our study identifies an essential role for the metabolite lactate in regulating macrophage responses to inflammation, which may be effectively targeted to treat inflammatory skin disorders such as psoriasis.

}, keywords = {Animals, Inflammation, Lactic Acid, Macrophages, Mice, Psoriasis, Skin}, issn = {1460-2075}, doi = {10.1038/s44318-024-00039-y}, author = {Ayyangar, Uttkarsh and Karkhanis, Aneesh and Tay, Heather and Afandi, Aliya Farissa Binte and Bhattacharjee, Oindrila and Ks, Lalitha and Lee, Sze Han and Chan, James and Raghavan, Srikala} } @article {1592, title = {Local release of tacrolimus from hydrogel-based drug delivery system is controlled by inflammatory enzymes in vivo and can be monitored non-invasively using in vivo imaging.}, journal = {PLoS One}, volume = {13}, year = {2018}, month = {2018}, pages = {e0203409}, abstract = {

BACKGROUND: Local drug delivery systems that adjust the release of immunosuppressive drug in response to the nature and intensity of inflammation represent a promising approach to reduce systemic immunosuppression and its side effects in allotransplantation. Here we aimed to demonstrate that release of tacrolimus from triglycerol monostearate hydrogel is inflammation-dependent in vivo. We further report that by loading the hydrogel with a near-infrared dye, it is possible to monitor drug release non-invasively in an in vivo model of vascularized composite allotransplantation.

MATERIALS AND METHODS: Inflammation was induced by local challenge with lipopolysaccharides in na{\"\i}ve rats 7 days after injection of tacrolimus-loaded hydrogel in the hind limb. Tacrolimus levels in blood and tissues were measured at selected time points. A near-infrared dye was encapsulated in the hydrogel together with tacrolimus in order to monitor hydrogel deposits and drug release in vitro and in vivo in a model of vascularized composite allotransplantation.

RESULTS: Injection of lipopolysaccharides led to increased blood and skin tacrolimus levels (p = 0.0076, day 7 vs. day 12 in blood, and p = 0.0007 in treated limbs, 48 h after injection compared to controls). Moreover, lipopolysaccharides-injected animals had higher tacrolimus levels in treated limbs compared to contralateral limbs (p = 0.0003 for skin and p = 0.0053 for muscle). Imaging of hydrogel deposits and tacrolimus release was achieved by encapsulating near-infrared dye in the hydrogel for 160 days. The correlation of tacrolimus and near-infrared dye release from hydrogel was R2 = 0.6297 and R2 = 0.5619 in blood and grafts of transplanted animals respectively and R2 = 0.6066 in vitro.

CONCLUSIONS: Here we demonstrate the inflammation-responsiveness of a tacrolimus-loaded hydrogel in vivo. Moreover, we show that encapsulating a near-infrared dye in the hydrogel provides a reliable correlation of tacrolimus and dye release from the hydrogel, and an accessible non-invasive method for monitoring drug release from hydrogel deposits.

}, keywords = {Animals, Drug Delivery Systems, Humans, Hydrogels, Immunosuppressive Agents, Inflammation, Male, Rats, Rats, Inbred BN, Rats, Inbred Lew, Tacrolimus}, issn = {1932-6203}, doi = {10.1371/journal.pone.0203409}, author = {Dzhonova, Dzhuliya and Olariu, Radu and Leckenby, Jonathan and Dhayani, Ashish and Vemula, Praveen Kumar and Prost, Jean-Christophe and Banz, Yara and Taddeo, Adriano and Rieben, Robert} } @article {1168, title = {Sterile Inflammation Enhances ECM Degradation in Integrin β1 KO Embryonic Skin.}, journal = {Cell Rep}, volume = {16}, year = {2016}, month = {2016 09 20}, pages = {3334-3347}, abstract = {

Epidermal knockout of integrin β1 results in complete disorganization of the basement membrane (BM), resulting in neonatal lethality. Here, we report that this disorganization is exacerbated by an early\ embryonic inflammatory response involving the recruitment of tissue-resident and monocyte-derived macrophages to the dermal-epidermal junction, associated with increased matrix metalloproteinase activity. Remarkably, the skin barrier in the integrin β1 knockout animals is intact, suggesting that this inflammatory response is initiated in a sterile environment. We demonstrate that the molecular mechanism involves de novo expression of integrin αvβ6 in the basal epidermal cells, which activates a TGF-β1 driven inflammatory cascade resulting in upregulation of dermal NF-κB in a Tenascin C-dependent manner. Importantly, treatment of β1 KO embryos in utero with small molecule inhibitors of TGF-βR1 and NF-κB results in marked rescue of the BM defects and amelioration of immune response, revealing an unconventional immuno-protective role for integrin β1 during BM remodeling.

}, keywords = {Animals, Extracellular Matrix, Inflammation, Integrin beta1, Macrophages, Mice, Mice, Knockout, Signal Transduction, Skin}, issn = {2211-1247}, doi = {10.1016/j.celrep.2016.08.062}, author = {Kurbet, Ambika S and Hegde, Samarth and Bhattacharjee, Oindrila and Marepally, Srujan and Vemula, Praveen K and Raghavan, Srikala} }