International Journal of Molecular Sciences, Jan 12, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Malaria is a major worldwide public health problem, with transmission occurring throughout Africa... more Malaria is a major worldwide public health problem, with transmission occurring throughout Africa, Asia, Oceania and Latin America. Over two billion people live in malarious areas of the world and it is estimated that 300-500 million cases and 1.5-2.7 million deaths occur annually. The increase in multi-drug resistant parasites and insecticide-resistant vectors has made the development of malaria vaccine a public health priority. The published genome offers tremendous opportunity for the identification of new antigens that can befast-tracked for vaccine development. We identified potential protein antigens present on the surface of asexual malaria blood stages through bioinformatics and published transcriptome and proteorne analysis. Amongst the proteins identified, we selected those that contain predicted a-helical coiled-coil regions, which are generally short and structurally stable as isolated fragments. Peptides were synthesized and used to immunize mice. Most peptides tested w...
There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbio... more There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbiome induced by isotretinoin in the pilosebaceous follicle of successfully treated patients can pave the way to identify novel therapeutic alternatives. We determined how the follicular microbiome changes with isotretinoin and identified which alterations correlate with a successful treatment response. Whole genome sequencing was done on casts from facial follicles of acne patients sampled before, during and after isotretinoin treatment. Alterations in the microbiome were assessed and correlated with treatment response at 20 weeks as defined as a 2‐grade improvement in global assessment score. We investigated the α‐diversity, β‐diversity, relative abundance of individual taxa, Cutibacterium acnes strain composition and bacterial metabolic profiles with a computational approach. We found that increased β‐diversity of the microbiome coincides with a successful treatment response to isotretin...
Mesenchymal stem cells (MSCs) have been postulated by a number of authors to be the precursor cel... more Mesenchymal stem cells (MSCs) have been postulated by a number of authors to be the precursor cells of fibroblasts and myofibroblasts in keloids. They have been seen as a regenerative pool that ensures a steady supply of cells. The objective of our study was to determine MSCs in keloids and normal skin as a determinant of keloid recurrence. Methods: This was a longitudinal prospective study in which patients with keloid excisions of their specimens analyzed for MSC. A control group of patients matched for age, sex, and body-mass index (BMI) with no history of keloids admitted for elective surgical procedures had their skin samples taken and also analyzed for MSCs. Data collected were analyzed and compared using Student's t, x 2 , and Fisher's exact t tests. Results: A total of 61 patients with keloids and a control group of 32 patients were recruited. The male:female ratio was 1:2 and mean age 29.5 and 29.7 years for keloids and controls, respectively. Patients with recurrent keloids had a mean density of 841.4 MSCs/g compared to 578 MSCs/g of tissue for those with no recurrence and 580 MSCs/g for patients with normal skin. Recurrent keloids had a significantly higher percentage of MSCs than those without. Conclusion: Keloids compared to normal skin had a higher percentage of MSCs, with recurrent keloids demonstrating an even higher count, a possible indicator that MSCs might correlate with severity of keloid disease and recurrence.
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis... more Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.
251, Treatment interruption did not impact efficacy or long-term safety of dupilumab: A phase 3 o... more 251, Treatment interruption did not impact efficacy or long-term safety of dupilumab: A phase 3 open-label trial. Lisa Beck et al. International Psoriasis Council Symposium: Scientific and Clinical Advances in Psoriasis: 2017 and Beyond 12:00 pm – 1:30 pm B113-116 1:05 pm Abstract #190, Pediatric psoriasis is an independent risk factor for comorbidity development Megha Tollefson, MD Medical Dermatology Society at the Society For Investigative Dermatology 12:00 pm – 1:45 pm A105-106 12:05 pm Abstract #189, Psoriasis age of onset: Effect on treatment outcomes in the PSOLAR registry. Sanminder Singh 12:29 pm Abstract #656, Changes of lesional and non-lesional skin microbiome in the treatment course of atopic dermatitis. Jung-Im Na, PhD 1:16 pm Abstract #308, Bone marrow/cord blood transplantation (BMCBT) ameliorates symptoms in some, but not all, subtypes of severe generalized junctional epidermolysis bullosa Jakub Tolar, MD/PhD Concurrent Mini-Symposium 6 Clinical Research: Patient Ou...
Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine chara... more Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses....
Staphylococcus aureus epicutaneous exposure to mouse skin was previously found to induce atopic d... more Staphylococcus aureus epicutaneous exposure to mouse skin was previously found to induce atopic dermatitis (AD)-like inflammation that was dependent upon IL-36 receptor (IL-36R) activity. However, whether systemic treatment with an anti-IL-36R blocking monoclonal antibody (mAb) could have a therapeutic effect by diminishing IL-36-dependent S. aureusinduced skin inflammation is unclear. Herein, we evaluated the efficacy of an IL-36R blocking mAb in inhibiting AD-like inflammation induced by S. aureus epicutaneous exposure to mouse skin. S. aureus epicutaneous exposure was performed by applying a S. aureus (1 x 10 8 CFU) soaked gauze pad for 7 days on dorsal skin while the mice were treated with systemic administration (intraperitoneal) of an anti-IL-36R blocking mAb or isotype control mAb on days-1, 2 and 5. The anti-IL-36R blocking mAb treatment resulted in significantly decreased AD-like skin inflammation as measured by disease score (edema, erythema, necrosis and scaling) by a blinded evaluator, epidermal thickness quantified from histologic sections, and decreased neutrophil recruitment but not total or IL-17-producing T cell (CD3+, gd, CD4+ and CD8+ T cell subsets) recruitment to the skin as measured by flow cytometry compared with isotype control-treated mice. Taken together, anti-IL-36R blocking mAb treatment inhibited AD-like skin inflammation induced by S. aureus epicutaneous exposure in a mechanism associated with decreased neutrophil but not T cell recruitment to the affected skin.
Objective: Negative pressure wound therapy (NPWT) has been widely used for a variety of wounds wi... more Objective: Negative pressure wound therapy (NPWT) has been widely used for a variety of wounds with good outcomes. However, it is contraindicated in the management of wounds with cerebrospinal fluid (CSF) leakages. The reason is the fear of a sudden shift of CSF fluid as a result of suction leading to brain herniation or coning. There is a paucity of data to either support or negate such claims. We aimed to determine the effect of NPWT in the management of patients with wounds with CSF leakages. Method: This was a longitudinal prospective study of patients having wounds with CSF leakages managed with NPWT in our institute. Outcome measures evaluated were changes in the level of consciousness, Glasgow Coma Scale (GCS) score, length of hospital stay, mean effluent collected, time taken for the wounds to heal/close and complications related to NPWT. Results: A total of 12 patients with wounds that had CSF leakage were managed with NPWT over two years. Of the patients, nine had wounds i...
The Journal of investigative dermatology, Nov 1, 2016
Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne... more Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne vulgaris and other infections. Recent work revealed that P. acnes clinical isolates can be classified into distinct phylotypes, several of which have associations with healthy skin or acne. We sought to determine if these phylotypes induce different immunological responses and express protein factors that may contribute to their disease associations. We found that acne-associated P. acnes phylotypes induced 2-3 fold higher levels of IFN-γ and IL-17 in peripheral blood mononuclear cells compared to healthy phylotypes. On the other hand, P. acnes phylotypes associated with healthy skin induced 2-4 fold higher levels of IL-10. Comparative proteomic analysis of P. acnes phylotypes revealed a differential expression of several proteins, including an adhesion protein that was expressed at least 10-fold higher in acne-associated phylotypes and a cell surface hydrolase expressed in all phylotyp...
IL-37 is an anti-inflammatory cytokine that is highly concentrated in the epidermis. In this stud... more IL-37 is an anti-inflammatory cytokine that is highly concentrated in the epidermis. In this study, we sought to investigate the immunomodulatory role of IL-37 in acne pathogenesis. In human monocytes isolated from peripheral blood mononuclear cells, we show that P. acnes upregulates expression of IL-37 in a pathway dependent on Toll-like receptor 2, NLRP3 and caspase-1 signal transduction. Using small interfering RNA to knock down IL-37 gene in monocytes, our results show upregulation of IL-1β, IL-6, and IL-8, and downregulation of IL-10, suggesting anti-inflammatory properties in P. acnes -stimulated monocytes. We demonstrate that IL-37 may have a reversal property when acting extracellularly. Recombinant IL-37 alone and P. acnes both induce IL-1β, IL-6, and IL-8 in a concentration-dependent manner. A greater cytokine response occurs when both IL-37 and P. acnes are used to co-treat monocytes. As we show that IL-37 is released only after cell membrane digest in monocytes but not actively secreted by viable cells, our data suggests a dualistic role of IL-37. While it may be anti-inflammatory intracellularly, IL-37 may act as a pro-inflammatory cytokine when released after cell damage and death. Intracellular IL-37 is a potent inhibitor of P. acnes -induced inflammatory response, yet has a reversal of properties when acting to signal nearby immune cells.
The Journal of investigative dermatology, Jan 14, 2015
Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 inflammasome was recently h... more Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we utilized an established nanotechnology capable of generating/releasing nitric oxide over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, though human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, TNF-α, IL-8 and IL-6 from human monocytes and IL-8 and IL-6 from human keratinocytes respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α, nor ...
Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflamm... more Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4(+), but not from CD8(+) T cells. Supernatants from P. acnes-stimulated PBMCs were sufficient to promote the differentiation of naive CD4(+)CD45RA T cells into Th17 cells. Furthermore, we found that the combination of IL-1β, IL-6, and transforming growth factor-β-neutralizing antibodies completely inhibited P. acnes-induced IL-17 production. Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from ...
We have recently described 95 predicted alpha-helical coiled-coil peptides derived from putative ... more We have recently described 95 predicted alpha-helical coiled-coil peptides derived from putative Plasmodium falciparum erythrocytic stage proteins. Seventy peptides recognized with the highest level of prevalence by sera from three endemic areas were selected for further studies. In this study, we sequentially examined antibody responses to these synthetic peptides in two cohorts of children at risk of clinical malaria in Kilifi district in coastal Kenya, in order to characterize the level of peptide recognition by age, and the role of anti-peptide antibodies in protection from clinical malaria. Antibody levels from 268 children in the first cohort (Chonyi) were assayed against 70 peptides. Thirty-nine peptides were selected for further study in a second cohort (Junju). The rationale for the second cohort was to confirm those peptides identified as protective in the first cohort. The Junju cohort comprised of children aged 1-6 years old (inclusive). Children were actively followed up to identify episodes of febrile malaria in both cohorts. Of the 70 peptides examined, 32 showed significantly (p<0.05) increased antibody recognition in older children and 40 showed significantly increased antibody recognition in parasitaemic children. Ten peptides were associated with a significantly reduced odds ratio (OR) for an episode of clinical malaria in the first cohort of children and two of these peptides (LR146 and AS202.11) were associated with a significantly reduced OR in both cohorts. LR146 is derived from hypothetical protein PFB0145c in PlasmoDB. Previous work has identified this protein as a target of antibodies effective in antibody dependent cellular inhibition (ADCI). The current study substantiates further the potential of protein PFB0145c and also identifies protein PF11_0424 as another likely target of protective antibodies against P. falciparum malaria.
International Journal of Molecular Sciences, Jan 12, 2023
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Malaria is a major worldwide public health problem, with transmission occurring throughout Africa... more Malaria is a major worldwide public health problem, with transmission occurring throughout Africa, Asia, Oceania and Latin America. Over two billion people live in malarious areas of the world and it is estimated that 300-500 million cases and 1.5-2.7 million deaths occur annually. The increase in multi-drug resistant parasites and insecticide-resistant vectors has made the development of malaria vaccine a public health priority. The published genome offers tremendous opportunity for the identification of new antigens that can befast-tracked for vaccine development. We identified potential protein antigens present on the surface of asexual malaria blood stages through bioinformatics and published transcriptome and proteorne analysis. Amongst the proteins identified, we selected those that contain predicted a-helical coiled-coil regions, which are generally short and structurally stable as isolated fragments. Peptides were synthesized and used to immunize mice. Most peptides tested w...
There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbio... more There are no drugs as effective as isotretinoin for acne. Deciphering the changes in the microbiome induced by isotretinoin in the pilosebaceous follicle of successfully treated patients can pave the way to identify novel therapeutic alternatives. We determined how the follicular microbiome changes with isotretinoin and identified which alterations correlate with a successful treatment response. Whole genome sequencing was done on casts from facial follicles of acne patients sampled before, during and after isotretinoin treatment. Alterations in the microbiome were assessed and correlated with treatment response at 20 weeks as defined as a 2‐grade improvement in global assessment score. We investigated the α‐diversity, β‐diversity, relative abundance of individual taxa, Cutibacterium acnes strain composition and bacterial metabolic profiles with a computational approach. We found that increased β‐diversity of the microbiome coincides with a successful treatment response to isotretin...
Mesenchymal stem cells (MSCs) have been postulated by a number of authors to be the precursor cel... more Mesenchymal stem cells (MSCs) have been postulated by a number of authors to be the precursor cells of fibroblasts and myofibroblasts in keloids. They have been seen as a regenerative pool that ensures a steady supply of cells. The objective of our study was to determine MSCs in keloids and normal skin as a determinant of keloid recurrence. Methods: This was a longitudinal prospective study in which patients with keloid excisions of their specimens analyzed for MSC. A control group of patients matched for age, sex, and body-mass index (BMI) with no history of keloids admitted for elective surgical procedures had their skin samples taken and also analyzed for MSCs. Data collected were analyzed and compared using Student's t, x 2 , and Fisher's exact t tests. Results: A total of 61 patients with keloids and a control group of 32 patients were recruited. The male:female ratio was 1:2 and mean age 29.5 and 29.7 years for keloids and controls, respectively. Patients with recurrent keloids had a mean density of 841.4 MSCs/g compared to 578 MSCs/g of tissue for those with no recurrence and 580 MSCs/g for patients with normal skin. Recurrent keloids had a significantly higher percentage of MSCs than those without. Conclusion: Keloids compared to normal skin had a higher percentage of MSCs, with recurrent keloids demonstrating an even higher count, a possible indicator that MSCs might correlate with severity of keloid disease and recurrence.
Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis... more Regulatory T cells (Tregs) play an important role in maintaining immune tolerance and homeostasis by modulating how the immune system is activated. Several studies have documented the critical role of Tregs in suppressing the functions of effector T cells and antigen-presenting cells. Under certain conditions, Tregs can lose their suppressive capability, leading to a compromised immune system. For example, mutations in the Treg transcription factor, Forkhead box P3 (FOXP3), can drive the development of autoimmune diseases in multiple organs within the body. Furthermore, mutations leading to a reduction in the numbers of Tregs or a change in their function facilitate autoimmunity, whereas an overabundance can inhibit anti-tumor and anti-pathogen immunity. This review discusses the characteristics of Tregs and their mechanism of action in select autoimmune skin diseases, transplantation, and skin cancer. We also examine the potential of Tregs-based cellular therapies in autoimmunity.
251, Treatment interruption did not impact efficacy or long-term safety of dupilumab: A phase 3 o... more 251, Treatment interruption did not impact efficacy or long-term safety of dupilumab: A phase 3 open-label trial. Lisa Beck et al. International Psoriasis Council Symposium: Scientific and Clinical Advances in Psoriasis: 2017 and Beyond 12:00 pm – 1:30 pm B113-116 1:05 pm Abstract #190, Pediatric psoriasis is an independent risk factor for comorbidity development Megha Tollefson, MD Medical Dermatology Society at the Society For Investigative Dermatology 12:00 pm – 1:45 pm A105-106 12:05 pm Abstract #189, Psoriasis age of onset: Effect on treatment outcomes in the PSOLAR registry. Sanminder Singh 12:29 pm Abstract #656, Changes of lesional and non-lesional skin microbiome in the treatment course of atopic dermatitis. Jung-Im Na, PhD 1:16 pm Abstract #308, Bone marrow/cord blood transplantation (BMCBT) ameliorates symptoms in some, but not all, subtypes of severe generalized junctional epidermolysis bullosa Jakub Tolar, MD/PhD Concurrent Mini-Symposium 6 Clinical Research: Patient Ou...
Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine chara... more Merkel cell carcinoma (MCC) is a rare and frequently lethal skin cancer with neuroendocrine characteristics. MCC can originate from either the presence of MCC polyomavirus (MCPyV) DNA or chronic ultraviolet (UV) exposure that can cause DNA mutations. MCC is predominant in sun-exposed regions of the body and can metastasize to regional lymph nodes, liver, lungs, bone, and brain. Older, light-skinned individuals with a history of significant sun exposure are at the highest risk. Previous studies have shown that tumors containing a high number of tumor-infiltrating T-cells have favorable survival, even in the absence of MCPyV DNA, suggesting that MCPyV infection enhances T-cell infiltration. However, other factors may also play a role in the host antitumor response. Herein, we review the impact of tumor infiltrating lymphocytes (TILs), mainly the CD4+, CD8+, and regulatory T-cell (Tregs) responses on the course of MCC, including their role in initiating MCPyV-specific immune responses....
Staphylococcus aureus epicutaneous exposure to mouse skin was previously found to induce atopic d... more Staphylococcus aureus epicutaneous exposure to mouse skin was previously found to induce atopic dermatitis (AD)-like inflammation that was dependent upon IL-36 receptor (IL-36R) activity. However, whether systemic treatment with an anti-IL-36R blocking monoclonal antibody (mAb) could have a therapeutic effect by diminishing IL-36-dependent S. aureusinduced skin inflammation is unclear. Herein, we evaluated the efficacy of an IL-36R blocking mAb in inhibiting AD-like inflammation induced by S. aureus epicutaneous exposure to mouse skin. S. aureus epicutaneous exposure was performed by applying a S. aureus (1 x 10 8 CFU) soaked gauze pad for 7 days on dorsal skin while the mice were treated with systemic administration (intraperitoneal) of an anti-IL-36R blocking mAb or isotype control mAb on days-1, 2 and 5. The anti-IL-36R blocking mAb treatment resulted in significantly decreased AD-like skin inflammation as measured by disease score (edema, erythema, necrosis and scaling) by a blinded evaluator, epidermal thickness quantified from histologic sections, and decreased neutrophil recruitment but not total or IL-17-producing T cell (CD3+, gd, CD4+ and CD8+ T cell subsets) recruitment to the skin as measured by flow cytometry compared with isotype control-treated mice. Taken together, anti-IL-36R blocking mAb treatment inhibited AD-like skin inflammation induced by S. aureus epicutaneous exposure in a mechanism associated with decreased neutrophil but not T cell recruitment to the affected skin.
Objective: Negative pressure wound therapy (NPWT) has been widely used for a variety of wounds wi... more Objective: Negative pressure wound therapy (NPWT) has been widely used for a variety of wounds with good outcomes. However, it is contraindicated in the management of wounds with cerebrospinal fluid (CSF) leakages. The reason is the fear of a sudden shift of CSF fluid as a result of suction leading to brain herniation or coning. There is a paucity of data to either support or negate such claims. We aimed to determine the effect of NPWT in the management of patients with wounds with CSF leakages. Method: This was a longitudinal prospective study of patients having wounds with CSF leakages managed with NPWT in our institute. Outcome measures evaluated were changes in the level of consciousness, Glasgow Coma Scale (GCS) score, length of hospital stay, mean effluent collected, time taken for the wounds to heal/close and complications related to NPWT. Results: A total of 12 patients with wounds that had CSF leakage were managed with NPWT over two years. Of the patients, nine had wounds i...
The Journal of investigative dermatology, Nov 1, 2016
Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne... more Propionibacterium acnes is a skin commensal bacterium that contributes to the development of acne vulgaris and other infections. Recent work revealed that P. acnes clinical isolates can be classified into distinct phylotypes, several of which have associations with healthy skin or acne. We sought to determine if these phylotypes induce different immunological responses and express protein factors that may contribute to their disease associations. We found that acne-associated P. acnes phylotypes induced 2-3 fold higher levels of IFN-γ and IL-17 in peripheral blood mononuclear cells compared to healthy phylotypes. On the other hand, P. acnes phylotypes associated with healthy skin induced 2-4 fold higher levels of IL-10. Comparative proteomic analysis of P. acnes phylotypes revealed a differential expression of several proteins, including an adhesion protein that was expressed at least 10-fold higher in acne-associated phylotypes and a cell surface hydrolase expressed in all phylotyp...
IL-37 is an anti-inflammatory cytokine that is highly concentrated in the epidermis. In this stud... more IL-37 is an anti-inflammatory cytokine that is highly concentrated in the epidermis. In this study, we sought to investigate the immunomodulatory role of IL-37 in acne pathogenesis. In human monocytes isolated from peripheral blood mononuclear cells, we show that P. acnes upregulates expression of IL-37 in a pathway dependent on Toll-like receptor 2, NLRP3 and caspase-1 signal transduction. Using small interfering RNA to knock down IL-37 gene in monocytes, our results show upregulation of IL-1β, IL-6, and IL-8, and downregulation of IL-10, suggesting anti-inflammatory properties in P. acnes -stimulated monocytes. We demonstrate that IL-37 may have a reversal property when acting extracellularly. Recombinant IL-37 alone and P. acnes both induce IL-1β, IL-6, and IL-8 in a concentration-dependent manner. A greater cytokine response occurs when both IL-37 and P. acnes are used to co-treat monocytes. As we show that IL-37 is released only after cell membrane digest in monocytes but not actively secreted by viable cells, our data suggests a dualistic role of IL-37. While it may be anti-inflammatory intracellularly, IL-37 may act as a pro-inflammatory cytokine when released after cell damage and death. Intracellular IL-37 is a potent inhibitor of P. acnes -induced inflammatory response, yet has a reversal of properties when acting to signal nearby immune cells.
The Journal of investigative dermatology, Jan 14, 2015
Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 inflammasome was recently h... more Propionibacterium acnes induction of IL-1 cytokines through the NLRP3 inflammasome was recently highlighted as a dominant etiological factor for acne vulgaris. Therefore, therapeutics targeting both the stimulus and the cascade would be ideal. Nitric oxide (NO), a potent biological messenger, has documented broad-spectrum antimicrobial and immunomodulatory properties. To harness these characteristics to target acne, we utilized an established nanotechnology capable of generating/releasing nitric oxide over time (NO-np). P. acnes was found to be highly sensitive to all concentrations of NO-np tested, though human keratinocyte, monocyte, and embryonic zebra fish assays revealed no cytotoxicity. NO-np significantly suppressed IL-1β, TNF-α, IL-8 and IL-6 from human monocytes and IL-8 and IL-6 from human keratinocytes respectively. Importantly, silencing of NLRP3 expression by small interfering RNA did not limit NO-np inhibition of IL-1 β secretion from monocytes, and neither TNF-α, nor ...
Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflamm... more Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs). P. acnes stimulated expression of key Th17-related genes, including IL-17A, RORα, RORc, IL-17RA, and IL-17RC, and triggered IL-17 secretion from CD4(+), but not from CD8(+) T cells. Supernatants from P. acnes-stimulated PBMCs were sufficient to promote the differentiation of naive CD4(+)CD45RA T cells into Th17 cells. Furthermore, we found that the combination of IL-1β, IL-6, and transforming growth factor-β-neutralizing antibodies completely inhibited P. acnes-induced IL-17 production. Importantly, we showed that IL-17-expressing cells were present in skin biopsies from acne patients but not from ...
We have recently described 95 predicted alpha-helical coiled-coil peptides derived from putative ... more We have recently described 95 predicted alpha-helical coiled-coil peptides derived from putative Plasmodium falciparum erythrocytic stage proteins. Seventy peptides recognized with the highest level of prevalence by sera from three endemic areas were selected for further studies. In this study, we sequentially examined antibody responses to these synthetic peptides in two cohorts of children at risk of clinical malaria in Kilifi district in coastal Kenya, in order to characterize the level of peptide recognition by age, and the role of anti-peptide antibodies in protection from clinical malaria. Antibody levels from 268 children in the first cohort (Chonyi) were assayed against 70 peptides. Thirty-nine peptides were selected for further study in a second cohort (Junju). The rationale for the second cohort was to confirm those peptides identified as protective in the first cohort. The Junju cohort comprised of children aged 1-6 years old (inclusive). Children were actively followed up to identify episodes of febrile malaria in both cohorts. Of the 70 peptides examined, 32 showed significantly (p<0.05) increased antibody recognition in older children and 40 showed significantly increased antibody recognition in parasitaemic children. Ten peptides were associated with a significantly reduced odds ratio (OR) for an episode of clinical malaria in the first cohort of children and two of these peptides (LR146 and AS202.11) were associated with a significantly reduced OR in both cohorts. LR146 is derived from hypothetical protein PFB0145c in PlasmoDB. Previous work has identified this protein as a target of antibodies effective in antibody dependent cellular inhibition (ADCI). The current study substantiates further the potential of protein PFB0145c and also identifies protein PF11_0424 as another likely target of protective antibodies against P. falciparum malaria.
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