2,907 Matching Annotations
  1. Jul 2021
    1. T RM cells producing IL-17A in resolved psoriasis epidermis could be associated with early relapse, and CD8 + T RM cells with IL-17A-producing potential in disease-naive, non lesional sites possibly correlate with disease duration.

      Arg-Met activates IL17A.

    2. CD103 + T RM cells produce IFN-gamma, IL-17A, and IL-22.

      Arg-Met activates IL22.

    3. T RM cells producing IL-17A in resolved psoriasis epidermis could be associated with early relapse, and CD8 + T RM cells with IL-17A-producing potential in disease-naive, non lesional sites possibly correlate with disease duration.

      Arg-Met activates CD8.

    1. On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

      beta-Defensins inhibits agouti.

    2. Conditional knockout of NFIB in HFSCs promotes McSCs proliferation and differentiation, indicating a role of NFIB as a regulator of McSC behavior 73.
    3. Conditional knockout of NFIB in HFSCs promotes McSCs proliferation and differentiation, indicating a role of NFIB as a regulator of McSC behavior 73.
    4. On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

      DSP inhibits agouti.

    5. On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

      CTNNB1 inhibits agouti.

    6. On the contrary, when agouti activity is inhibited by beta-Defensin, or Corin, or beta-catenin in the DP, the yellow coat turns to be black XREF_BIBR - XREF_BIBR.

      CORIN inhibits agouti.

    7. Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

      TGFB1 inhibits Integrins.

    8. Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

      Wnt inhibits CTNNB1.

    9. Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

      Wnt inhibits Wnt.

    10. Even the melanocyte progenitors emigrate into feathers, the differentiation may be suppressed by agouti, made by the peripheral pulp fibroblasts 1.

      Agouti inhibits cell differentiation.

    11. Pax3 not only promotes melanogenesis by activating the expression of MITF, but also maintains McSCs quiescence by competing with MITF through binding an enhancer responsible for the expression of dopachrome tautomerase (DCT), an intermediate in the biosynthesis of melanin.

      PAX3 increases the amount of MITF.

    12. Alx3 decreases melanin production by directly suppressing the expression of MITF, by indirectly inhibiting the secretion of Edn3, and by indirectly promoting the expression of ASIP.

      ALX3 increases the amount of MITF.

    13. Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.

      WNT3A increases the amount of MITF.

    14. Inhibition of NFIB signaling in HFSCs directly stimulates expression of endothelin 2 (Edn2), which is required in HFSCs dependent McSCs activation.

      NFIB decreases the amount of EDN2.

    15. For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

      Modified MITF decreases the amount of TGFBR.

    16. Alx3 decreases melanin production by directly suppressing the expression of MITF, by indirectly inhibiting the secretion of Edn3, and by indirectly promoting the expression of ASIP.

      ALX3 decreases the amount of ASIP.

    17. For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

      Modified MIR211 decreases the amount of TGFB.

    18. For example, MITF dependent expression of microRNA-211 promotes pigmentation in melanoblast and melanocyte cell lines by inhibiting the expression of TGF-beta receptor 2, which is involved in the maintenance of McSCs quiescence.

      Modified MIR211 decreases the amount of TGFBR.

    19. Through interacting with PAX3, FOXD3 prevents binding of PAX3 to MITF promoter to repress melanogenesis in zebrafish, quail and chick neural crest cells XREF_BIBR, XREF_BIBR, suggesting that down-regulation of Foxd3 is a crucial step during the early phase of melanoblast lineage specification from neural crest cells.

      MITF binds PAX3.

    20. In human melanoma cells, MITF also interacts directly with beta-catenin and redirects beta-catenin transcriptional activity away from target genes regulated by Wnt and beta-catenin signaling, toward MITF specific target promoters to activate transcription 57.

      CTNNB1 binds MITF.

    21. TGF-beta binds TGF-beta receptors in melanocytes, leading to the phosphorylation of downstream effector Smad2, which inhibits melanocyte growth and melanogenesis through downregulating PAX3 and MITF transcription XREF_BIBR, XREF_BIBR.

      TGFB binds TGFBR.

    22. Notch ligands including Jagged1, Jagged2, Delta-like1, Delta-like3 and Delta-like4 bind to Notch receptor, which induces signal transduction cascade through the induction of transcription factor RBP-JK to initiate the transcription of target genes 69.

      Notch binds Notch.

    23. UV and ionizing radiation induced DNA damage triggers McSC differentiation, leading to McSC exhaustion and hair graying XREF_BIBR, XREF_BIBR, XREF_BIBR.
    24. Although alpha-MSH can derive from epithelial cells and systematically, the activation of Mc1r signaling by alpha-MSH is in the DP, which further regulates melanocyte pigmentation.

      POMC activates MC1R.

    25. These data indicate that MITF may enhance the role of Wnt and beta-catenin signaling in proliferation and differentiation of McSCs in a feedback mechanism.

      MITF activates CTNNB1.

    26. Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.
    27. These data indicate that MITF may enhance the role of Wnt and beta-catenin signaling in proliferation and differentiation of McSCs in a feedback mechanism.

      MITF activates Wnt.

    28. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.
    29. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.
    30. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.
    31. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.
    32. Continuous activation of beta-catenin Signaling in McSCs promotes McSCs differentiation, exhaustion and premature hair graying 8.
    33. In human melanoma cells, MITF also interacts directly with beta-catenin and redirects beta-catenin transcriptional activity away from target genes regulated by Wnt and beta-catenin signaling, toward MITF specific target promoters to activate transcription 57.
    34. Sox10, Pax3, and Wnt3a mediated Wnt and beta-catenin signaling induce the transcription of MITF and promote differentiation of neural crest into melanoblasts XREF_BIBR - XREF_BIBR, though MITF is not expressed in the neural crest.

      WNT3A activates Wnt.

    35. Inhibition of Wnt signaling by a Wnt antagonist secreted frizzled related protein 4 (sFRP4), which is exclusively expressed in the epithelial cells but not the melanocytes of the hair follicle, results in a decrease of melanocytes differentiation in the regenerating hair follicle 79.

      SFRP4 activates Wnt.

    36. PDGF promotes the proliferation of human melanoblasts and differentiation of melanocytes 104, indicating that adipose secreted PDGF may also regulate McSCs activation and differentiation.
    37. Mechanistically, knockout of Kindlin-1 promotes cutaneous epithelial stem cells differentiation via inhibiting alpha (v) beta (6) integrin mediated TGF-beta1 liberation and promoting integrin independent Wnt ligand expression to activate Wnt and beta-catenin signaling 82.

      Integrins activates TGFB1.

    38. Injecting Wnt inhibitor DKK1 into skin inhibits TPA induced the proliferation and differentiation of McSCs 52.
    39. Injecting Wnt inhibitor DKK1 into skin inhibits TPA induced the proliferation and differentiation of McSCs 52.
    40. So the white color can be due to the absence of melanocytes by non migration or death of melanocytes, or due to the suppression of differentiation by agouti or other inhibitors.

      Agouti activates cell differentiation.

    41. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.

      End3 activates cell differentiation.

    42. HGF, SCF, and End3 have been revealed to promote melanoblast or melanocyte proliferation and differentiation XREF_BIBR, XREF_BIBR.
    1. This is attributable at least in part to TRPV4 function in keratinocytes, where calcium influx through this channel triggers ERK phosphorylation.

      calcium(2+) leads to the phosphorylation of ERK.

    2. The absence of TRPA1 has also been shown to reduce scratching behaviors in the acetone-ether-water mouse model of dry skin and chronic itch [XREF_BIBR].

      TRPA1 inhibits Pruritus.

    3. Consistent with this observation, IL31 receptors were found to be colocalized with both TRPA1 and TRPV1 in sensory neurons, and genetic elimination of either channel reduced IL31 induced itch [XREF_BIBR].

      IL31 inhibits Pruritus.

    4. These authors showed that application of the TRPV3 agonists eugenol or 2-APB to either cultured human hair follicles or outer root sheath (ORS) keratinocytes, produced a dose dependent suppression of proliferation and induction of apoptosis in both systems.
    5. It has also been reported that either chemical or thermal TRPM8 activation can reduce PGE2 release from human keratinocytes in response to UVB irradiation [XREF_BIBR].
    6. In organ cultures of these hair follicles, activation of TRPV1 suppressed epithelial proliferation and hair shaft elongation and promoted hair follicle regression [XREF_BIBR].
    7. Two different stimuli that are known to promote keratinocyte differentiation, elevations in extracellular calcium and 1, 25, dihydroxyvitamin D3, both upregulate transcription of TRPV6 [XREF_BIBR].

      dihydroxy-vitamin D3 increases the amount of TRPV6.

    8. In these cells, capsaicin could evoke the release of IL8 and prostaglandin E2 (PGE2) and upregulate the expression of cyclooxygenase 2 (COX2), providing evidence for potential proinflammatory activities.

      capsaicin increases the amount of PTGS2.

    9. Conversely, factors that suppress TRPV3 activity include oxygen dependent hydroxylation of TRPV3 by Factor-inhibiting-hypoxia inducible factor [XREF_BIBR].

      dioxygen hydroxylates TRPV3.

    10. In some chemotherapy induced neuropathy models, mechanical hyperalgesia appears to involve alterations in the interactions between TRPV4, alpha2beta1 integrin, and src kinase [XREF_BIBR].

      SRC binds TRPV4.

    11. In some chemotherapy induced neuropathy models, mechanical hyperalgesia appears to involve alterations in the interactions between TRPV4, alpha2beta1 integrin, and src kinase [XREF_BIBR].

      Integrins binds TRPV4.

    12. In some chemotherapy induced neuropathy models, mechanical hyperalgesia appears to involve alterations in the interactions between TRPV4, alpha2beta1 integrin, and src kinase [XREF_BIBR].

      Integrins binds SRC.

    13. Unlike full-length TRPM8, eTRPM8 protein is confined to the endoplasmic reticulum, where it functions as a calcium release channel that facilitates elevations in calcium within adjacent mitochondria in response to canonical TRPM8 stimuli such as icilin, menthol, or cold.

      Menthol activates TRPM8.

    14. Unlike full-length TRPM8, eTRPM8 protein is confined to the endoplasmic reticulum, where it functions as a calcium release channel that facilitates elevations in calcium within adjacent mitochondria in response to canonical TRPM8 stimuli such as icilin, menthol, or cold.

      icilin activates TRPM8.

    15. While it is possible that TRPM1 activity, per se, contributes to melanoma progression and invasiveness, a more likely mechanism arises from the fact that miRNA 211, a tumor suppressor miRNA, is encoded in one of the introns of the TRPM1 gene and its transcription is co-regulated with that of TRPM1 [XREF_BIBR].
    16. Given that TRPA1 and TRPV1 produce similar effects of cellular depolarization and calcium influx, it is interesting to compare these effects of TRPA1 activation with those described above for TRPV1, where channel activation appears to delay barrier recovery.

      TRPA1 activates calcium(2+).

    17. For example, thymic stromal lymphopoietin (TSLP), which is released by keratinocytes in response to histaminergic signaling, activates neuronal TRPA1 downstream of the TSLP receptor [XREF_BIBR].

      TSLP activates TRPA1.

    18. For example, thymic stromal lymphopoietin (TSLP), which is released by keratinocytes in response to histaminergic signaling, activates neuronal TRPA1 downstream of the TSLP receptor [XREF_BIBR].

      TSLP activates CRLF2.

    19. There is also a growing body of evidence suggesting that TRPV3 is a key contributor to epidermal homeostasis and skin sensory function in certain pathological conditions.
    20. This effect is partially keratinocyte-autonomous, since it was observed in keratinocyte conditional TRPV4 knockout animals, and since TRPV4 mediates calcium entry into cultured mouse keratinocytes upon UVB exposure [XREF_BIBR].

      TRPV4 activates calcium(2+).

    21. Two different stimuli that are known to promote keratinocyte differentiation, elevations in extracellular calcium and 1, 25, dihydroxyvitamin D3, both upregulate transcription of TRPV6 [XREF_BIBR].
    22. TRPV1 Epidermal Upregulation in Human Skin Diseases.

      TRPV1 activates Disease.

    23. Given that TRPA1 and TRPV1 produce similar effects of cellular depolarization and calcium influx, it is interesting to compare these effects of TRPA1 activation with those described above for TRPV1, where channel activation appears to delay barrier recovery.

      TRPV1 activates calcium(2+).

    24. Moreover, pharmacological or genetic blockade of SP signaling was shown to attenuate the inflammatory response associated with contact dermatitis [XREF_BIBR].
    25. Indeed, they found that activation of TRPV3 in keratinocytes triggers the protease mediated shedding of the EGFR ligand, TGF-alpha.

      Protease activates EGFR_ligand.

    26. At least part of the acute pain component in the former model is attributable to activation of TRPA1 by streptozotocin generated peroxynitrite [XREF_BIBR].

      streptozocin activates TRPA1.

    27. In one study, oxazolone induced ear edema was increased in mice lacking TRPV1 or in wild-type mice in which TRPV1 expressing neurons were desensitized with vanilloid compounds [XREF_BIBR].
    28. When overexpressed recombinantly in cell lines, TRPV1 can be activated by capsaicin, the major pungent ingredient in chili peppers, or by related chemical compounds that share a vanilloid chemical group, thus providing the " transient receptor vanilloid " subfamily its name [XREF_BIBR].

      capsaicin activates TRPV1.

    29. Many non electrophillic chemicals, including certain anesthetics (e.g., propophol, isofluorane, lidocaine), fenamate nonsteroidal anti-inflammatory drugs, cannabinoids (e.g., increment (9)-Tetrahydrocannabinol), cooling agents (e.g., icillin), and intracellular calcium ions can also activate TRPA1, presumably via more conventional ligand-receptor interactions.

      calcium(2+) activates TRPA1.

    30. First, mitochondrial calcium influx enhances synthesis of adenosine triphosphate, which when released from keratinocytes might alter their proliferation and differentiation in an autocrine manner.

      calcium(2+) activates ATP.

    31. However, in addition to its conventional transcription mediated mechanisms of action, testosterone appears to activate TRPM8 by directly binding to the extracellular domain of the channel.

      testosterone activates TRPM8.

    1. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGAE.

    2. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R inhibits ITGA1.

    3. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CD69 inhibits S1PR1.

    4. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGAE.

    5. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F inhibits ITGA1.

    6. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGAE.

    7. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 inhibits ITGA1.

    8. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of IL23R.

    9. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      ITGAE increases the amount of CCR6.

    10. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    11. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of PRF1.

    12. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      ITGA1 increases the amount of GZMB.

    13. Accordingly, IL-15-dependent expression of perforin and granzyme B was augmented by IL-6, but not other cytokine combinations tested (XREF_SUPPLEMENTARY C-S2E).

      IL6 increases the amount of GZMB.

    14. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of PRF1.

    15. Rather, their cytotoxic capacity was primed through IL-2 and IL-15-mediated induction of perforin and granzyme B expression.

      IL2 increases the amount of GZMB.

    16. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    17. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of PRF1.

    18. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of IL17A.

    19. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      CD8 increases the amount of GZMB.

    20. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of IL23R.

    21. Further validating transcriptional data, CXCR3 expression was higher on CD8 + CD103 + CD49a + Trm cells, whereas IL-23R and CCR6 were preferentially expressed by CD8 + CD103 + CD49a - Trm cells (XREF_FIG G).

      CD8 increases the amount of CCR6.

    22. Moreover, IL-15 stimulation potentiated TCR dependent expression of IL-17 and IFN-gamma by epidermal CD8 + CD103 + CD49a - and IFN-gamma by CD8 + CD103 + CD49a + Trm cells, respectively (XREF_FIG D), substantiating effectual gamma chain receptor signaling in both subsets.

      CD8 increases the amount of TCR.

    23. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    24. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of PRF1.

    25. In addition, CD8 + CD49a + Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response.

      Trm increases the amount of GZMB.

    26. CD103 binds E-cadherin, which is highly expressed on epithelia, whereas CD69 antagonizes sphingosine 1-phosphate receptor 1 (S1PR1)-mediated egress from tissues.

      CDH1 binds ITGAE.

    27. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates ITGAE.

    28. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      IV activates IFNG.

    29. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGAE activates IL17A.

    30. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates ITGAE.

    31. Relative to the epidermal CD8 + CD103 + CD49a - Trm cells, dermal counterparts produced 3.5-fold less IL-17.

      ITGA1 activates IL17A.

    32. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IL17A.

    33. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates IFNG.

    34. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      ITGA1 activates IFNG.

    35. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      ITGA1 activates IFNG.

    36. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      ITGA1 activates Trm.

    37. IL-2 and IL-15 Induce Cytotoxic Effector Protein Expression in Epidermal CD8 + CD103 + CD49a + Trm Cells.

      IL2 activates Trm.

    38. Conversely, CD8 + CD49a - Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease.
    39. This functional dichotomy was evident in the comparison of distinct immune mediated skin diseases, with skin biopsies from vitiligo patients showing a predominance of cytotoxic CD8 + CD103 + CD49a + Trm cells while skin biopsies from psoriasis patients featured the accumulation of the IL-17 producing CD8 + CD103 + CD49a - counterparts.

      IL17A activates CD8.

    40. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGAE.

    41. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      IL15 activates ITGA1.

    42. Generally, IFN-gamma contributes to immunity toward intracellular infections while IL-17 provides anti-fungal defense and both of these cytokines initiate inflammatory keratinocyte responses.

      IFNG activates immune response.

    43. In line withincreased CD49a frequencies, IFN-gamma producing Trm cells were enriched in vitiligo lesions (XREF_FIG G).

      IFNG activates Trm.

    44. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL23R activates IL17A.

    45. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      IL17F activates IL17A.

    46. Nonetheless, transcripts of genes associated with IL-17 production, such as IL17F, RORC, IL23R, and CCR6, were significantly decreased in CD8 + CD103 + CD49a + relative to CD8 + CD103 + CD49a - Trm cells, whereas transcripts for IFN-gamma were elevated (XREF_FIG D-E).

      CCR6 activates IL17A.

    47. TCR engagement using anti-CD3 antibodies also preferentially induced IFN-gamma by epidermal CD8 + CD103 + CD49a + Trm cells (XREF_FIG D).

      TCR activates Trm.

    48. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGAE.

    49. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates ITGA1.

    50. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      CD8 activates Trm.

    51. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates ITGAE.

    52. Collagen IV mediated engagement of CD49a enhanced IFN-gamma production by CD8 + CD103 + CD49a + Trm cells, possibly through stabilizing IFNG transcripts.

      Collagen activates IFNG.

    53. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates IL2.

    54. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      carbon atom activates TNF.

    55. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates IL2.

    56. Revealing functional specialization among epidermal Trm cells with respect to CD49a expression, CD8 + CD103 + CD49a - Trm cells preferentially produced IL-17, a cytokine required for control of bacterial and fungal infections.

      Trm activates IL17A.

    57. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IL17A.

    58. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IL17A.

    59. Corroborating transcriptional profiles, CD8 + CD103 + CD49a - Trm cells produced IL-17 while CD8 + CD103 + CD49a + Trm cells excelled in IFN-gamma production upon stimulation with phorbol 12-myristate 13-acetate and ionomycin (XREF_FIG A-6C).

      Trm activates IL17A.

    60. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IL17A.

    61. Here, we identify CD49a expression as a marker delineating a subpopulation ofCD8 + Trm cells in human skin that specifically localize to thebasal layer of epidermis, preferentially produce IFN-gamma, and display high cytotoxic capacity upon stimulation.

      Trm activates IFNG.

    62. Moreover, IL-17 or IFN-gamma production by distinct Trm cells subsets was generally maintained even in the context of the vigorous tissue inflammation.

      Trm activates IFNG.

    63. In human skin epithelia, CD8 + CD49a + Trm cells produced interferon-gamma, whereas CD8 + CD49a - Trm cells produced interleukin-17 (IL-17).

      Trm activates IFNG.

    64. Thus, CD49a expression delineated a dichotomy in Trm cell cytokine production, augmented by IL-15, with CD8 + CD103 + CD49a - and CD8 + CD103 + CD49a + Trm cells preferentially producing IL-17 and IFN-gamma, respectively.

      Trm activates IFNG.

    65. TNF and IL-2 were abundantly produced by dermal and epidermal Trm cell subsets (XREF_FIG B and 6C).

      Trm activates TNF.

    1. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      MAVS translocates to the mitochondrion.

    2. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      NLRP3 translocates to the mitochondrion.

    3. By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

      RIPK2 leads to the phosphorylation of ULK1.

    4. Conversely, others have shown that overexpression of NLRP7 inhibited pro-IL-1beta synthesis and secretion.

      NLRP7 inhibits IL1B.

    5. Some studies have suggested that NLRP12 may negatively regulate the NF-kappaB pathway.

      NLRP12 inhibits NFkappaB.

    6. IFNgamma functions via signal transducer and activator of transcription 1 (STAT1) and can not induce NLRC5 expression in the absence of STAT1.

      IFNG increases the amount of NLRC5.

    7. It was recently shown that MAVS recruits NLRP3 to the mitochondria for activation in response to non crystalline activators and that microtubule driven trafficking of the mitochondria is necessary for NLRP3 and ASC complex assembly and activation.

      STS binds NLRP3.

    8. NOD1 and 2 both interact with RIPK2, via a CARD-CARD homotypic interaction.

      RIPK2 binds NOD1.

    9. In Alzheimer 's disease, amyloid-beta aggregates were shown to activate NLRP3 ex vivo in primary macrophages and microglia.

      APP activates NLRP3.

    10. The possibility of a role for NOD2 in non bacterial infections has also been suggested, with NOD2 having been shown to induce an IFNbeta driven antiviral response following recognition of single stranded viral RNA.

      NOD2 activates IFNB1.

    11. IL-1beta produced downstream of the NLRP3 inflammasome, which is also stimulated by islet amyloid polypeptide, promotes beta-cell dysfunction, and cell death, linking NLRP3 activation to insulin resistance.

      IAPP activates NLRP3.

    12. Moreover, it was recently reported that bacterial acylated lipopeptides (acLP) activated NLRP7 and stimulated formation of an NLRP7-ASC-caspase-1 inflammasome.

      AEBP1 activates NLRP7.

    13. NLRX1 has been shown to enhance ROS production when it is overexpressed, following Chlamydia and Shigella infection, as well as in response to TNFalpha and poly (I : C).
    14. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates NLRP3.

    15. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM3 activates calcium(2+).

    16. Mutations in NLRP3 were reported to induce an overproduction of IL-1beta that triggers the subsequent development of severe inflammation.

      NLRP3 activates IL1B.

    17. Ceballos-Olvera et al. demonstrated that while IL-18 and pyroptosis are both essential for host resistance, the production of IL-1beta by NLRP3 was deleterious, as it triggered excessive neutrophil recruitment and exacerbated the disease.

      NLRP3 activates IL1B.

    18. Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.
    19. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      TRPM2 activates NLRP3.

    20. By triggering the phosphorylation of the autophagy inducer ULK1, RIPK2 induces autophagy of disrupted mitochondria (mitophagy), preventing the accumulation of ROS and NLRP3 inflammasome activation.

      RIPK2 activates autophagy.

    21. Nlrp6 - / - mice had increased numbers of immune cells in their circulation, as well as enhanced activation of MAPK and NF-kappaB signaling, though Toll like receptor (TLR) activation, suggesting that NLRP6 may suppress TLR pathways after the recognition of pathogens to prevent amplified inflammatory pathology.

      TLR activates NFkappaB.

    22. Other NLRs such as NOD1, NOD2, NLRP10, NLRX1, NLRC5, and CIITA do not directly engage the inflammatory caspases, but instead activate nuclear factor-kappaB (NF-kappaB), mitogen activated protein kinases (MAPKs), and interferon (IFN) regulatory factors (IRFs) to stimulate innate immunity.
    23. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    24. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    25. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    26. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    27. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.
    28. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    29. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    30. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    31. The exact mechanism of NLRP3 activation by uric acid crystals is still unknown, but monosodium urate and calcium pyrophosphate dihydrate crystals were found to induce NLRP3 and caspase-1 activation and the subsequent processing of IL-1beta and IL-18.
    32. Ceramide, a specific product from the metabolism of long-chain saturated fatty acids, and the saturated free fatty acid, palmitate, have been shown to induce IL-1beta in an NLRP3 dependent fashion [Ref.

      ceramide activates IL1B.

    33. Crystalline cholesterol was proposed to cause atherosclerosis by acting as a danger signal and initiating inflammation through the NLRP3 inflammasome.
    34. A recent study by Zhong et al. suggested that particulate stimuli might induce mitochondrial production of reactive oxygen species (ROS), which triggers a calcium influx mediated by transient receptor potential melastatin 2 (TRPM2) to activate NLRP3.

      dioxygen activates calcium(2+).

    1. PTEN and PTPs all antagonize the insulin signaling as they directly interact with PI3K and IR [XREF_BIBR], and both consist of a cysteine residue in the active site that is highly susceptible to H 2 O 2 -induced oxidation.

      PTEN inhibits INS.

    2. For instance, H 2 O 2 can induce PTEN oxidation, which inactivates PTEN phosphatase function by establishing a Cys 124 -Cys 71 disulfide bond [XREF_BIBR].

      PTEN inhibits Phosphatase.

    3. For example, the Parkinson disease protein 7 (PARK7) was found to repress the PTEN phosphatase function by binding to PTEN.

      PARK7 inhibits PTEN.

    4. Recently, it has been found that the impairment of PARK2 can induce the suppression of PTEN by S nitrosylation through increase the level of NO [XREF_BIBR].

      PRKN activates PTEN.

    5. Besides, Prx II deficient MEFs induced PTEN oxidation and increased PI3K and Akt activation when exposed to insulin, which leads to an increase the insulin sensitivity.

      PRX activates PTEN.

    6. Prx III-deficiency also induces the augmentation in both PTEN oxidation and Trx dimerization.

      PRX activates PTEN.

    1. It has been demonstrated that Prx I can preserve and promote the tumor-suppressive function of PTEN by preventing oxidation of PTEN under benign oxidative stress via direct interaction.

      PRX activates PTEN.

    2. Also, Prx II deficient cells increased PTEN oxidation and insulin sensitivity.

      PRX activates PTEN.

    1. To examine whether FoxO3a is required for PTEN mediated negative regulation of autophagy, we analyzed the mRNA levels of ATG5, ATG7, and ATG12 in the ipsilateral hippocampus post-ICH.

      PTEN inhibits autophagy.

    2. In the present study, PTEN inhibition not only reduced the levels of autophagy related proteins but also activated the PI3K and AKT pathway in the ipsilateral hippocampus after ICH.

      PTEN inhibits PI3K.

    3. Specifically, PTEN antagonized the PI3K and AKT signaling and downstream effector FoxO3a phosphorylation and subsequently enhanced nuclear translocation of FoxO3a to drive proautophagy gene program, but these changes were diminished upon PTEN inhibition.

      PTEN leads to the dephosphorylation of FOXO3.

    4. Mechanistically, blockage of PTEN could enhance FoxO3a phosphorylation modification to restrict its nuclear translocation and ATG transcription via activating the PI3K and AKT pathway, leading to the suppression of the autophagic program.

      PTEN leads to the dephosphorylation of FOXO3.

    5. According to these data, we speculate that posthemorrhagic PTEN elevation triggers the nuclear accumulation of FoxO3a and subsequent transcriptional activation of ATGs, resulting in sequential activation of autophagy.

      PTEN activates FOXO3.

    6. Herein, we identified that ICH induced a significant increase in ATG transcriptional levels including ATG5, ATG7, and ATG12, which was strongly associated with PTEN mediated FoxO3a nuclear translocation.

      PTEN activates FOXO3.

    7. PTEN Inhibition Reverses Secondary Hippocampal Injury Post-ICH.
    8. Also, inactivation of the PI3K/AKT/mTOR pathway has been implicated in PTEN induced autophagy initiation [XREF_BIBR, XREF_BIBR].

      PTEN activates autophagy.

    1. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of JNK.

    2. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of JNK.

    3. S100A8 Induced Pro Inflammatory Cytokine Production Via Phosphorylation of ERK and JNK in BV-2 Cells.

      S100A8 leads to the phosphorylation of ERK.

    4. Also, the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular-signal-regulated kinase (ERK) were stimulated by S100A8, which had an analogous effect to the lipopolysaccharide (LPS) treatment (XREF_FIG C-E).

      S100A8 leads to the phosphorylation of ERK.

    5. The S100A8 knockdown using shRNA revealed that COX-2 and PGE 2 expression was regulated by S100A8, which suggested that the intracellular increase of microglial S100A8 levels upregulated COX-2 expression and PGE2 secretion, contributing to neuronal death under hypoxic conditions.

      S100A8 increases the amount of PTGS2.

    6. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL6.

    7. In agreement with previous reports, the results of this study confirmed that S100A8 significantly increased the production of IL-6, TNF-alpha, and IL-1beta.

      S100A8 activates IL1B.

    1. Knockdown of S100A8 levels by using shRNA revealed that microglial S100A8 expression activated COX-2 expression, leading to neuronal apoptosis under hypoxia.

      S100A8 increases the amount of PTGS2.

    2. S100A8, secreted from neurons under hypoxia, activated the secretion of tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) through phosphorylation of extracellular-signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) in microglia.

      S100A8 activates IL6.