Macrophage accumulation is a critical step during development of chronic inflammation, initiating progression of many devastating diseases. Leukocyte-specific integrin αDβ2 (CD11d/CD18) is dramatically upregulated on macrophages at inflammatory sites. Previously we found that CD11d overexpression on cell surfaces inhibits in vitro cell migration due to excessive adhesion. Here we have investigated how inflammation-mediated CD11d upregulation contributes to macrophage retention at inflammatory sites during atherogenesis. Atherosclerosis was evaluated in CD11d−/−/ApoE−/− mice after 16 weeks on a Western diet. CD11d deficiency led to a marked reduction in lipid deposition in aortas and isolated macrophages. Macrophage numbers in aortic sinuses of CD11d−/− mice were reduced without affecting their apoptosis and proliferation. Adoptive transfer of fluorescently-labeled wild-type and CD11d−/− monocytes into ApoE−/− mice demonstrated similar recruitment from circulation, but reduced accumulation of CD11d−/− macrophages within the aortas. Furthermore, CD11d expression was significantly upregulated on macrophages in atherosclerotic lesions and M1 macrophages in vitro. Interestingly, expression of the related ligand-sharing integrin CD11b was not altered. This difference defines their distinct roles in the regulation of macrophage migration. CD11d-deficient M1 macrophages demonstrated improved migration in a three-dimensional fibrin matrix and during resolution of peritoneal inflammation, while migration of CD11b−/− M1 macrophages was not affected. These results prove the contribution of high densities of CD11d to macrophage arrest during atherogenesis. Since high expression of CD11d was detected in several inflammation-dependent diseases, we suggest that CD11d/CD18 upregulation on pro-inflammatory macrophages may represent a common mechanism for macrophage retention at inflammatory sites, thereby promoting chronic inflammation and disease development.

Nonmelanoma skin cancer is the most frequently diagnosed malignancy in the United States, and multiple exposures to solar ultraviolet (UV) radiation (particularly its UV-B component, 290-320 nm), is its major cause. 'Chemoprevention' by naturally occurring agents is being appreciated as a newer dimension in the management of neoplasia including skin cancer. We recently demonstrated that resveratrol (trans-3, 5, 4-trihydroxystilbene), an antioxidant found in grapes, red wines and a variety of nuts and berries, imparts protection from acute UV-B-mediated cutaneous damages in SKH-1 hairless mice. Understanding the mechanism of resveratrol-mediated protection of UV responses is important. We earlier demonstrated that resveratrol imparts chemopreventive effects against multiple UV-exposure-mediated modulations in (1) cki-cyclin-cdk network, and (2) mitogen activated protein kinase (MAPK)-pathway. This study was conducted to assess the involvement of inhibitor of apoptosis protein family Survivin during resveratrol-mediated protection from multiple exposures of UV-B (180 mJ/cm(2); on alternate days; for a total of seven exposures) radiations in the SKH-1 hairless mouse skin. Our data demonstrated that topical pre-treatment of resveratrol (10 micromol in 200 microl acetone/mouse) resulted in significant inhibition of UV-B exposure-mediated increases in (1) cellular proliferations (Ki-67 immunostaining), (2) protein levels of epidermal cyclooxygenase-2 and ornithine decarboxylase, established markers of tumor promotion, (3) protein and messenger RNA levels of Survivin, and (4) phosphorylation of survivin in the skin of SKH-1 hairless mouse. Resveratrol pretreatment also resulted in (1) reversal of UV-B-mediated decrease of Smac/DIABLO, and (2) enhancement of UV-B-mediated induction of apoptosis, in mouse skin. Taken together, our study suggested that resveratrol imparts chemopreventive effects against UV-B exposure-mediated damages in SKH-1 hairless mouse skin via inhibiting Survivin and the associated events.

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SummarySkin cancer is a major health problem worldwide. It is the most common cancer in the United States and poses a significant healthcare burden. Excessive UVR exposure is the most common cause of skin cancer. Despite various precautionary measures to avoid direct UVR exposure, the incidence of skin cancer and mortality related to it remains high. Furthermore, the current treatment options are expensive and have side effects including toxicity to normal cells. Thus, a safe and effective approach is needed to prevent and treat skin cancer. Chemopreventive strategy using naturally occurring compounds, such as resveratrol, is a promising approach to reduce the incidence of UVR-induced skin cancer and delay its progression. This review highlights the current body of evidence related to chemopreventive role of resveratrol and its molecular mechanisms in UVR-induced skin carcinogenesis. K E Y W O R D Schemoprevention, resveratrol, skin carcinogenesis, UVR | INTRODUCTIONSkin is the largest organ in the human body, which serves many essential functions including protection from environmental stressors, infections, and regulating body temperature and fluids. 1 In addition, it acts as a huge sensory receptor for touch, heat, cold, pain, and pressure.Furthermore, it is the first line of defense and provides immunological surveillance against germs, allergens, and irritants trying to enter the body. 2 Healthy skin is also vital for visual appearance and psychosocial communication. 3,4 Therefore, continuous preventive measures are required to protect skin against disfiguring, function impairing, or lifethreatening consequences.Skin is primarily composed of 3 layers (epidermis, dermis, and subcutaneous). The epidermis is the outer protective layer of skin, which consists of squamous and basal cells. Melanocytes are also found in epidermis, which are cells containing pigments and allow the skin to tan. The dermis which is just below the epidermis contains blood vessels, connective tissue, hair follicles, and sweat glands. The subcutaneous layer (also known as the hypodermis or subcutis) is the deepest layer of the skin containing fat cells and collagens. Skin cancer occurs when there is uncontrolled growth of abnormal cells in any of these 3 layers of skin. 5,6 Skin cancer is the most common cancer in the United States. 7,8 It has been reported that one in 5 Americans will develop skin cancer in their lifetime. 9-13 It poses significant healthcare burden, with estimated annual cost of treating nonmelanoma and melanoma skin cancer being $4.8 and $3.3 billion, respectively, in the United States. 8 Several factors can influence the risk of developing skin cancer such as excessive solar UV exposure, skin type, family and personal history of skin cancer, frequent use of tanning bed, multiple moles, history of sunburns, and others. 14 There are 3 most common forms of skin cancers that are distinguished by the types of cells affected. Most skin cancers arise from epidermal layer. Basal cell carcinoma is the most common type of ski...

BackgroundThe development of chronic inflammation depends on the balance between accumulation of pro‐inflammatory, classically activated (M1) and alternatively activated (M2) macrophages within the injured tissue. The mesenchymal migration and accumulation of macrophages in the inflamed sites largely depend on myeloid‐specific αMβ2 and αDβ2 integrins, which share similar ligands but have different densities on different subsets of macrophages. The level of integrin expression regulates cell migration. Namely, a low‐intermediate expression supports cell motility, while a high expression generates strong adhesion that prevents cell migration. In this project, we tested how αMβ2 and αDβ2 integrins are involved in the migration and retention of M1 and M2 macrophages at the site of inflammation.Method and ResultsTo test our hypothesis, wild type (WT), αD−/− and αM−/− mice were intraperitoneally injected with thioglycollate to generate macrophages. Isolated macrophages were treated with IFN‐γ and IL‐4 for 4 days to activate M1 and M2 phenotypes, respectively. Integrin levels on macrophages were evaluated by qPCR and FACS. We found that the expression of αD was strongly upregulated on M1 macrophages, but not on M2 macrophages, while the level of αM remained unchanged on both subsets. To test the effect of integrins on the migration of M1 and M2 macrophages, we labeled cells with red and green fluorescent dyes and applied in vitro migration assay in 3D fibrin matrix.Our results showed that WT M2 macrophages possess significantly stronger migratory properties compared to WT M1 macrophages. To understand the contribution of individual integrins we used αD−/− and αM−/− macrophages. The results demonstrated that while αM‐deficiency had no significant effect, αD‐deficiency improved the migration of M1 macrophages. In contrast, both αD‐ and αM‐deficiency reduced the migration of M2 macrophages. To verify these results, we tested in vivo macrophage migration using the model of resolution of peritoneal inflammation. M1 and M2 macrophages, labeled with red and green fluorescent dyes respectively, were injected into the peritoneal cavity of mice with induced peritoneal inflammation. After 3 days, we evaluated the ability of macrophages to emigrate from the peritoneal cavity to lymphatics. Our results corresponded to our in vitro migratory assay. M2 macrophages emigrate significantly faster, αD‐deficiency improves the efflux of M1 macrophages and αD‐ and αM‐deficiency reduced the emigration of M2 macrophages.ConclusionTaken together, these data suggest that integrin αM, which has an intermediate expression on M1 and M2 macrophages, supports macrophage migration. In contrast, integrin αD, which has a high expression on M1 macrophages, prevents the migration of these cells and can promote the retention of M1 macrophages in the inflamed sites. Therefore, integrin αD is a potential therapeutic target to prevent pro‐inflammatory macrophage accumulation and development of chronic inflammation.Support or Funding InformationThis project is funded by NIH and the project number is 5R01DK102020‐05This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.