Publications by authors named "Joseph Kirma"

7 Publications

  • Page 1 of 1

IRAK2 has a critical role in promoting feed-forward amplification of epidermal inflammatory responses.

J Invest Dermatol 2021 Apr 14. Epub 2021 Apr 14.

Department of Dermatology, University of Michigan, Ann Arbor, Michigan, 48109, USA. Electronic address:

Many inflammatory skin diseases are characterized by altered epidermal differentiation. Whether this altered differentiation promotes inflammatory responses has been unknown. Here we show that IRAK2, a member of the signaling complex downstream of IL-1/IL-36, correlates positively with disease severity in both AD and psoriasis. Inhibition of epidermal IRAK2 normalizes differentiation and inflammation in two mouse models of psoriasis- and AD-like inflammation. Specifically, we demonstrate that IRAK2 ties together pro-inflammatory and differentiation dependent responses and show that this function of IRAK2 is specific to keratinocytes and acts through the differentiation associated transcription factor ZNF750. Taken together, our findings suggest that IRAK2 has a critical role in promoting feed-forward amplification of inflammatory responses in skin through modulation of differentiation pathways and inflammatory responses.
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http://dx.doi.org/10.1016/j.jid.2021.03.019DOI Listing
April 2021

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis.

JCI Insight 2020 10 2;5(19). Epub 2020 Oct 2.

Division of Rheumatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.
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http://dx.doi.org/10.1172/jci.insight.139930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566715PMC
October 2020

TNF-α regulates diabetic macrophage function through the histone acetyltransferase MOF.

JCI Insight 2020 03 12;5(5). Epub 2020 Mar 12.

Department of Surgery.

A critical component of wound healing is the transition from the inflammatory phase to the proliferation phase to initiate healing and remodeling of the wound. Macrophages are critical for the initiation and resolution of the inflammatory phase during wound repair. In diabetes, macrophages display a sustained inflammatory phenotype in late wound healing characterized by elevated production of inflammatory cytokines, such as TNF-α. Previous studies have shown that an altered epigenetic program directs diabetic macrophages toward a proinflammatory phenotype, contributing to a sustained inflammatory phase. Males absent on the first (MOF) is a histone acetyltransferase (HAT) that has been shown be a coactivator of TNF-α signaling and promote NF-κB-mediated gene transcription in prostate cancer cell lines. Based on MOF's role in TNF-α/NF-κB-mediated gene expression, we hypothesized that MOF influences macrophage-mediated inflammation during wound repair. We used myeloid-specific Mof-knockout (Lyz2Cre Moffl/fl) and diet-induced obese (DIO) mice to determine the function of MOF in diabetic wound healing. MOF-deficient mice exhibited reduced inflammatory cytokine gene expression. Furthermore, we found that wound macrophages from DIO mice had elevated MOF levels and higher levels of acetylated histone H4K16, MOF's primary substrate of HAT activity, on the promoters of inflammatory genes. We further identified that MOF expression could be stimulated by TNF-α and that treatment with etanercept, an FDA-approved TNF-α inhibitor, reduced MOF levels and improved wound healing in DIO mice. This report is the first to our knowledge to define an important role for MOF in regulating macrophage-mediated inflammation in wound repair and identifies TNF-α inhibition as a potential therapy for the treatment of chronic inflammation in diabetic wounds.
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http://dx.doi.org/10.1172/jci.insight.132306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141388PMC
March 2020

Metabolomic identification of placental alterations in fetal growth restriction.

J Matern Fetal Neonatal Med 2020 Feb 10:1-10. Epub 2020 Feb 10.

Department of Obstetrics and Gynecology, Beaumont Health, Royal Oak, Michigan, USA.

Fetal growth restriction (FGR), viz., birth weight <10th percentile is a common pregnancy complication which increases the risk of adverse fetal and newborn outcomes. The placenta is the key organ for fetal growth as it controls oxygen and nutrient availability. This study aims to elucidate the mechanisms of and identify putative placental biomarkers for FGR using high-resolution metabolomics. Placenta samples from 19 FGR cases and 30 controls were analyzed using proton magnetic resonance (H NMR) spectroscopy and direct flow injection mass spectrometry with reverse-phase liquid-chromatography mass spectrometry (DI-LC-MS/MS). Significant concentration differences (-value <.05) in 179 of the 220 metabolites were measured. Of the 179 metabolites, 176 (98.3%) had reduced placental levels in FGR cases. The best performing metabolite model: 3-hydroxybutyrate, glycine and PCaaC42:0 achieved an AUC (95% CI) = 0.912 (0.814-1.000) with a sensitivity of 86.7% and specificity of 84.2% for FGR detection. Metabolite set enrichment analysis (MSEA) revealed significant ( < .05) perturbation of multiple placental metabolite pathways including urea metabolism, ammonia recycling, porphyrin metabolism, bile acid biosynthesis, galactose metabolism and perturbed protein biosynthesis. The placental metabolic pathway analysis revealed abnormalities that are consistent with fetal hepatic dysfunction in FGR. Near global reduction of metabolite concentrations was found in the placenta from FGR cases and metabolites demonstrated excellent diagnostic accuracy for FGR detection.
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http://dx.doi.org/10.1080/14767058.2020.1722632DOI Listing
February 2020

Application of H-NMR Metabolomics for the Discovery of Blood Plasma Biomarkers of a Mediterranean Diet.

Metabolites 2019 Sep 27;9(10). Epub 2019 Sep 27.

Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Belfast BT9 5DL, UK.

The Mediterranean diet (MD) is a dietary pattern well-known for its benefits in disease prevention. Monitoring adherence to the MD could be improved by discovery of novel dietary biomarkers. The MEDiterranean Diet in Northern Ireland (MEDDINI) intervention study monitored the adherence of participants to the MD for up to 12 months. This investigation aimed to profile plasma metabolites, correlating each against the MD score of participants (n = 58). Based on an established 14-point scale MD score, subjects were classified into two groups ("low" and "high"). H-Nuclear Magnetic Resonance (H-NMR) metabolomic analysis found that citric acid was the most significant metabolite ( = 5.99 × 10*; = 0.03), differing between 'low' and 'high'. Furthermore, five additional metabolites significantly differed ( < 0.05; < 0.35) between the two groups. Discriminatory metabolites included: citric acid, pyruvic acid, betaine, mannose, acetic acid and -inositol. Additionally, the top five most influential metabolites in multivariate models were also citric acid, pyruvic acid, betaine, mannose and -inositol. Metabolites significantly correlated with the consumption of certain food types. For example, citric acid positively correlated fruit, fruit juice and vegetable constituents of the diet, and negatively correlated with sweet foods alone or when combined with carbonated drinks. Citric acid was the best performing biomarker and this was enhanced by paired ratio with pyruvic acid. The present study demonstrates the utility of metabolomic profiling for effectively assessing adherence to MD and the discovery of novel dietary biomarkers.
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http://dx.doi.org/10.3390/metabo9100201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836148PMC
September 2019

Integrated Proteomic and Metabolomic prediction of Term Preeclampsia.

Sci Rep 2017 11 23;7(1):16189. Epub 2017 Nov 23.

Harris Birthright Research Centre for Fetal Medicine, King's College Hospital, London, UK.

Term preeclampsia (tPE), ≥37 weeks, is the most common form of PE and the most difficult to predict. Little is known about its pathogenesis. This study aims to elucidate the pathogenesis and assess early prediction of tPE using serial integrated metabolomic and proteomic systems biology approaches. Serial first- (11-14 weeks) and third-trimester (30-34 weeks) serum samples were analyzed using targeted metabolomic (H NMR and DI-LC-MS/MS) and proteomic (MALDI-TOF/TOF-MS) platforms. We analyzed 35 tPE cases and 63 controls. Serial first- (sphingomyelin C18:1 and urea) and third-trimester (hexose and citrate) metabolite screening predicted tPE with an area under the receiver operating characteristic curve (AUC) (95% CI) = 0.817 (0.732-0.902) and a sensitivity of 81.6% and specificity of 71.0%. Serial first [TATA box binding protein-associated factor (TBP)] and third-trimester [Testis-expressed sequence 15 protein (TEX15)] protein biomarkers highly accurately predicted tPE with an AUC (95% CI) of 0.987 (0.961-1.000), sensitivity 100% and specificity 98.4%. Integrated pathway over-representation analysis combining metabolomic and proteomic data revealed significant alterations in signal transduction, G protein coupled receptors, serotonin and glycosaminoglycan metabolisms among others. This is the first report of serial integrated and combined metabolomic and proteomic analysis of tPE. High predictive accuracy and potentially important pathogenic information were achieved.
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http://dx.doi.org/10.1038/s41598-017-15882-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700929PMC
November 2017

A Health Profile of Arab Americans in Michigan: A Novel Approach to Using a Hospital Administrative Database.

J Immigr Minor Health 2016 12;18(6):1449-1454

Minority Outreach Program, Beaumont Cancer Institute, Royal Oak, MI, USA.

The objectives of this study were to estimate and compare the prevalence of heart disease, cancer, chronic lower respiratory disease, stroke, Alzheimer's, diabetes, nephrosis, flu/pneumonia, hypertension, and atherosclerosis between Arab Americans and whites attending a large, metropolitan hospital system. The sample included 68,047 patients, 18 years of age or older, who visited the hospital during 2012. Demographic and disease variables were electronically abstracted. Demographic characteristics were compared between Arab Americans and whites using Chi square tests. Sex specific, age-adjusted prevalence ratios (PR) and 95 % confidence intervals were estimated for these two groups using a log-binomial regression model. Compared to white men, Arab American men had a higher prevalence of diabetes (PR 1.40, 95 % CI 1.29-1.52) and hypertension (PR 1.07, 95 % CI 1.04-1.10), and a lower prevalence of chronic lower respiratory disease (PR 0.74, 95 % CI 0.66-0.83). Compared to white women, Arab American women had a higher prevalence of chronic lower respiratory disease (PR 1.12, 95 % CI 1.01-1.25), diabetes (PR 1.49, 95 % CI 1.38-1.60), influenza/pneumonia (PR 1.26, 95 % CI 1.05-1.51) and hypertension (PR 1.04, 95 % CI 1.01-1.08). This study supports previous findings that health disparities exist for Arab Americans, who are classified as "white" in health statistics. Standard inclusion of Arab American as a separate ethnicity category will aid researchers in assessing the health care needs of this growing minority community.
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http://dx.doi.org/10.1007/s10903-015-0296-8DOI Listing
December 2016