IU Indianapolis ScholarWorks :: Browsing by Author "Turner, Matthew J."

Browsing by Author "Turner, Matthew J."

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Allergic airway recall responses require IL-9 from resident memory CD4+ T cells
(American Association for the Advancement of Science, 2022) Ulrich, Benjamin J.; Kharwadkar, Rakshin; Chu, Michelle; Pajulas, Abigail; Muralidharan, Charanya; Koh, Byunghee; Fu, Yongyao; Gao, Hongyu; Hayes, Tristan A.; Zhou, Hong-Ming; Goplen, Nick P.; Nelson, Andrew S.; Liu, Yunlong; Linnemann, Amelia K.; Turner, Matthew J.; Licona-Limón, Paula; Flavell, Richard A.; Sun, Jie; Kaplan, Mark H.; Microbiology and Immunology, School of Medicine
Asthma is a chronic inflammatory lung disease with intermittent flares predominately mediated through memory T cells. Yet, the identity of long-term memory cells that mediate allergic recall responses is not well defined. In this report, using a mouse model of chronic allergen exposure followed by an allergen-free rest period, we characterized a subpopulation of CD4+ T cells that secreted IL-9 as an obligate effector cytokine. IL-9-secreting cells had a resident memory T cell phenotype, and blocking IL-9 during a recall challenge or deleting IL-9 from T cells significantly diminished airway inflammation and airway hyperreactivity. T cells secreted IL-9 in an allergen recall-specific manner, and secretion was amplified by IL-33. Using scRNA-seq and scATAC-seq, we defined the cellular identity of a distinct population of T cells with a proallergic cytokine pattern. Thus, in a recall model of allergic airway inflammation, IL-9 secretion from a multicytokine-producing CD4+ T cell population was required for an allergen recall response.
Bcl6 and Blimp1 reciprocally regulate ST2+ Treg-cell development in the context of allergic airway inflammation
(Elsevier, 2020) Koh, Byunghee; Ulrich, Benjamin J.; Nelson, Andrew S.; Panangipalli, Gayathri; Kharwadkar, Rakshin; Wu, Wenting; Xie, Markus M.; Fu, Yongyao; Turner, Matthew J.; Paczesny, Sophie; Janga, Sarath Chandra; Dent, Alexander L.; Kaplan, Mark H.; Pediatrics, School of Medicine
Background Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. Objective The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. Methods We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. Results In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine–producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg–cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. Conclusions During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.
Capecitabine-induced lichenoid drug eruption: a case report
(University of California, 2017) Gehlhausen, Jeff R.; Strausburg, Matthew B.; Aouthmany, Mouhammad; Katona, Terrence M.; Turner, Matthew J.; Dermatology, School of Medicine
Capecitabine is a 5-fluorouracil basedchemotherapeutic drug widely used in the treatmentof solid tumors, especially colorectal and breast. Someof the most common side effects of capecitabine arecutaneous in nature, including hand-foot syndrome(palmar-plantar erythrodysesthesia). Several reports inthe literature link capecitabine use with photosensitivelichenoid eruptions. Herein, we present a case ofcapecitabine-induced lichenoid eruption in an elderlyfemale with metastatic breast cancer and discuss ourfindings in relationship to previously reported cases ofthis and other capecitabine-induced skin pathologies.
Cigarette smoke exposure mediated generation of Platelet-activating factor agonists induces systemic immunosuppression
(Office of the Vice Chancellor for Research, 2012-04-13) Sahu, Ravi P.; Turner, Matthew J.; Konger, Raymond L.; Travers, Jeffrey B.
The ubiquitous environmental pollutant cigarette smoke (CS) is known to exert immodulatory effects. CS also acts as a potent pro-oxidative stressor. Several studies including ours have characterized the importance of various pro-oxidative stressors including UVB to inhibit host immunity and an importance of the platelet-activating factor (1-alkyl-2-acetyl-glycerophosphocholine; PAF), a potent lipid mediator in this process. PAF is produced enzymatically in a tightly-controlled process. In addition, oxidative stressors can act directly on glycerophosphocholines (GPC) to produce oxidized GPC which are potent PAF-R agonists. The present studies employed model systems consisting of PAF-receptor (PAF-R)-expressing (KBP) and–deficient (KBM) cells and mice (wild type [WT] and Pafr-/-) to determine whether CS exposure could generate PAF-R agonists in blood and whether it could suppress contact hypersensitivity reactions in a PAF-R-dependent manner. We show that lipid extracts derived from the blood of CS-treated WT mice resulted in immediate intracellular calcium (Ca2+2+mice. This inhibitory effect of CS in WT mice were similar to those induced by a PAF-R agonist, CPAF or histamine. Furthermore, this inhibition of CHS by CS in WT mice was blocked by antioxidants vitamin C and N-acetyl cysteine. These findings indicate that CS exposure induces systemic immunosuppression in a PAF-R-dependent manner. These studies provide the first evidence that the pro-oxidative stressor CS can modulate cutaneous immunity via the generation of PAF agonists through lipid oxidation.) mobilization response only in KBP cells. However, no Camobilization response was detected with lipid extracts from non-smoked (sham) mice both in KBP and KBM cells. In addition, lipid extracts only from CS-treated mice induced an increase in IL-8 secretion in KBP cells indicating that CS generates systemic PAF-R agonists. CS exposure also inhibited contact hypersensitivity to the allergen dinitrofluorobenzene (DNFB) selectively in WT but not inPafr-/-
Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen
(National Academy of Sciences, 2019-04-30) Deak, Peter E.; Kim, Baksun; Qayum, Amina Abdul; Shin, Jaeho; Vitalpur, Girish; Kloepfer, Kirsten M.; Turner, Matthew J.; Smith, Neal; Shreffler, Wayne G.; Kiziltepe, Tanyel; Kaplan, Mark H.; Bilgicer, Basar; Pediatrics, School of Medicine
Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.
Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin
(MDPI, 2021-08-11) Konger, Raymond L.; Derr-Yellin, Ethel; Zimmers, Teresa A.; Katona, Terrence; Xuei, Xiaoling; Liu, Yunlong; Zhou, Hong-Ming; Simpson, Ed Ronald, Jr.; Turner, Matthew J.; Pathology and Laboratory Medicine, School of Medicine
Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling.
Ex vivo culture of mouse skin activates an interleukin 1 alpha-dependent inflammatory response
(Wiley, 2020-01) Zhou, Hong-Ming; Slominski, Radomir M.; Seymour, Leroy J.; Bell, Maria C.; Dave, Priya; Atumonye, Joseph; Wright, William, III.; Dawes, Avery; Griesenauer, Brad; Paczesny, Sophie; Kaplan, Mark H.; Spandau, Dan F.; Turner, Matthew J.; Dermatology, School of Medicine
Ex vivo culture of mouse and human skin causes an inflammatory response characterized by production of multiple cytokines. We used ex vivo culture of mouse tail skin specimens to investigate mechanisms of this skin culture-induced inflammatory response. Multiplex assays revealed production of interleukin 1 alpha (IL-1α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), chemokine C-X-C motif ligand 1 (CXCL1), granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) during skin culture, and quantitative PCR revealed transcripts for these proteins were also increased. Ex vivo cultures of skin from myeloid differentiation primary response 88 deficient mice (Myd88-/- ) demonstrated significantly reduced expression of transcripts for the aforementioned cytokines. The same result was observed with skin from interleukin 1 receptor type 1 deficient mice (Il1r1-/- ). These data suggested the IL-1R1/MyD88 axis is required for the skin culture-induced inflammatory response and led us to investigate the role of IL-1α and IL-1β (the ligands for IL-1R1) in this process. Addition of IL-1α neutralizing antibody to skin cultures significantly reduced expression of Cxcl1, Il6 and Csf3. IL-1β neutralization did not reduce levels of these transcripts. These studies suggest that IL-1α promotes the skin the culture-induced inflammatory response.
Exposure: Staphylococcus aureus skin colonization predisposes to food allergy in the Learning Early about Allergy to Peanut (LEAP) and LEAP-On studies
(Elsevier, 2019-08) Cook-Mills, Joan M.; Kaplan, Mark H.; Turner, Matthew J.; Kloepfer, Kirsten M.; Kumar, Rajesh; Pediatrics, School of Medicine
GCN2 EIF2 Kinase is Critical for Keratinocyte Collective Migration and Wound Healing
(2021-12) Miles, Rebecca Ruth; Wek, Ronald C.; Spandau, Dan F.; Kaplan, Mark H.; Turner, Matthew J.; Heuer, Josef G.
A critical factor in the healing of a cutaneous wound is the closure of the wound bed that is accomplished by collectively migrating keratinocytes. Wounds that fail to heal appropriately are a significant burden on patient well-being as well as healthcare systems. Further understanding of the molecular pathways involved in wound healing is needed to find new treatments to accelerate healing and reduce treatment costs. Previously, we demonstrated that the integrated stress response (ISR) is critical for keratinocyte response to multiple stresses. Because wounding and repair mechanisms can induce stresses in the skin, we hypothesized that the ISR plays a central role in wound healing. The ISR features a family of stress-activated protein kinases phosphorylate the translation factor eIF2 (eIF2α-P), resulting in diminished global protein synthesis coincident with preferential translation of gene transcripts that lead to the remedy of the stress. Wounding of immortalized NTERT human keratinocyte monolayers led to rapid activation of the eIF2 kinase GCN2, and subsequent eIF2α-P and translational control. Deletion of GCN2 in wounding assays diminished eIF2α-P and translational control during wound healing. Global transcriptome analysis of wounded keratinocytes revealed that deletion of GCN2 induced a compensatory unfolded protein response and dysregulation of mRNAs important for cellular migration. Pathway analysis suggested that GCN2 is necessary for proper activation of key signaling networks and subsequent coordination of RAC-GTP driven reactive oxygen species (ROS) generation following wounding. Additionally, amino acid control of cysteine is regulated by GCN2. We therefore investigated ROS levels following wounding and observed that GCN2 was required for proper ROS induction and actin reorganization in leading edge keratinocytes and that these changes were coincident with reduced RAC and RHO activation and cysteine depletion. The loss of leading-edge ROS in GCN2-deleted cells can be phenocopied with NOX inhibition. Lastly, mice deleted for GCN2 exhibited delayed wound healing compared to WT controls in an excisional wound healing model. These results indicate that GCN2 is required for the induction of collective cell migration and plays a critical role in coordinating the re-epithelialization of cutaneous wounds. We propose the ISR is a potential therapeutic target in chronic wounds.
Human keratinocytes utilize the integrated stress response to adapt to environmental stress
(2017-06) Collier, Ann E.; Spandau, Dan F.; Wek, Ronald C.; Travers, Jeffrey B.; Turchi, John J.; Turner, Matthew J.
Human skin, consisting of the outer epidermis and inner dermis, serves as a barrier that protects the body from an onslaught of environmental stresses. Keratinocytes in the stratified epidermis undergo sequential differentiation that consists of multiple layers of cells differing in structure and function. Therefore, keratinocytes must not only combat environmental stress, but need to undergo massive changes in gene expression and morphology to form a proper barrier. One mode by which cells cope with stress and differentiation is through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α-P), which causes global inhibition of protein synthesis coincident with preferential translation of select gene transcripts. Translational repression allows stressed cells to conserve energy and prioritize pro-survival processes to alleviate stress damage. Since eIF2α kinases are each activated by distinct types of stress, this pathway is referred to as the Integrated Stress Response (ISR). We sought to identify the roles of the ISR in the keratinocyte response to the stresses associated with differentiation and ultraviolet B (UVB) irradiation. In this thesis, we show that both general and gene-specific translational control in the ISR are activated following differentiation or UVB irradiation of human keratinocytes. ISR deficiency through genetic modifications or pharmacological interventions caused severe divergence from the appropriate keratinocyte response to differentiation or UVB. Differentiation genes were selectively translated by eIF2α-P, and inhibition of the ISR diminished their induction during differentiation. Furthermore, loss of the eIF2α kinase GCN2 (EIF2AK4) adversely affected the ability of keratinocytes to stratify in three dimensional cultures. Our analysis also revealed a non-canonical ISR response following UVB irradiation, in which downstream factors ATF4 (CREB2) and CHOP (DDIT3/GADD153) were poorly expressed due to repressed transcription, despite preferential translation in response to eIF2α-P. The ISR was cytoprotective during UVB and we found that eIF2α-P was required for a UVB induced G1 arrest, cell fate determination, and DNA repair via a mechanism involving translational control of human CDKN1A (p21 protein) transcript variant 4 mRNA. Collectively, this thesis describes novel roles for the ISR in keratinocyte differentiation and response to UVB, emphasizing the utility of targeting translational control in skin disease therapy.

Browsing by Author "Turner, Matthew J."

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