Th17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPC’s role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases. ### Competing Interest Statement The authors have declared no competing interest. The raw data from RNA-seq was deposited at Sequence read archive - SRA under the accession code: PRJNA1160718

Skin wounds are an important clinical problem which affects millions of people worldwide. The search for new therapeutic approaches to improve wound healing is needed. The present study aimed to evaluate the effects of the oral treatment with the skin-related probiotics Lactobacillus johnsonii LA1 (LJ), L. paracasei ST11 (LP), and L. rhamnosus LPR (LR) in a model of excisional skin wounds in Swiss mice. The animals received daily oral gavage of PBS or 1 × 107 colony-forming units of LJ, LP, or LR, singly, beginning just after the creation of wounds until euthanasia. Blood flow was evaluated by laser Doppler perfusion imaging. Myeloperoxidase and N-acetyl-β-D-glucosaminidase activities were used to assess the accumulation of neutrophils and macrophages, respectively. The wound tissue was also collected for histological analyses (H&E, Toluidine blue, and Picrosirius red staining). The macroscopic wound closure rate was faster only in mice treated with LR, but not with LJ and LP, when compared to mice treated with PBS. Histological evaluations showed that treatment with LR stimulated wound epithelization when compared to PBS. Further analyses showed that wounds from LR-treated mice presented a significant decrease in macrophage (p < 0.001) and mast cell (p < 0.001) infiltration, along with improved angiogenesis (p < 0.001) and blood flow (p < 0.01). Of note, collagen deposition and scarring were reduced in LR-treated mice when compared to PBS-treated mice. In conclusion, our results show that the oral treatment with Lactobacillus rhamnosus accelerates skin wound closure and reduces scar, besides to reducing inflammation and fibrogenesis and improving angiogenesis in the wounded skin.

DNA is naturally very unstable and several agents are capable of damaging and altering its structure, thus leading to several negative consequences. Therefore, this review seeks to better understand the relationship between different DNA repair mechanisms and metabolic pathways, and how such a relationship can influence the outcome of different human inflammatory diseases. Studies have shown that factors involved in DNA repair are also involved in the regulation of cellular metabolism in response to DNA damage. Indeed, it was demonstrated that cells deficient in DNA repair have abrupt rewiring of cell metabolism. Additionally, oxidative stress observed in several human disorders increase DNA damage that contributes in metabolic changes and diseases progression. DNA molecule is daily exposed to several types of damages and, in mammal cells, the DNA damage response (DDR) is responsible to monitor and repair genotoxic stress. The activation of DDR mostly depends on the DNA damage type and involves the activation of sensors, transducers, and effector proteins. The effector protein pathways are closely linked to several cell biology processes, such as apoptosis, senescence, cell cycle control, inflammatory response, and gene transcriptions. Recently, it was demonstrated that DDR genes are involved in cell metabolism and contribute to DNA repair and cell survival. Understanding as DNA damage impacts in cell function is important to comprehend and treat several human inflammatory diseases.

The microvasculature heterogeneity is a complex subject in vascular biology. The difficulty of building a dynamic and interactive view among the microenvironments, the cellular and molecular heterogeneities, and the basic aspects of the vessel formation processes make the available knowledge largely fragmented. The neovascularisation processes, termed vasculogenesis, angiogenesis, arteriogenesis, and lymphangiogenesis, are important to the formation and proper functioning of organs and tissues both in the embryo and the postnatal period. These processes are intrinsically related to microvascular cells, such as endothelial and mural cells. These cells are able to adjust their activities in response to the metabolic and physiological requirements of the tissues, by displaying a broad plasticity that results in a significant cellular and molecular heterogeneity. In this review, we intend to approach the microvasculature heterogeneity in an integrated view considering the diversity of neovascularisation processes and the cellular and molecular heterogeneity that contribute to microcirculatory homeostasis. For that, we will cover their interactions in the different blood-organ barriers and discuss how they cooperate in an integrated regulatory network that is controlled by specific molecular signatures.