title: Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1α-Dependent miR-155 Suppression.
abstract: Lactic acid (LA) is present in tumors, asthma, and wound healing, environments with elevated IL-33 and mast cell infiltration. Although IL-33 is a potent mast cell activator, how LA affects IL-33-mediated mast cell function is unknown. To investigate this, mouse bone marrow-derived mast cells were cultured with or without LA and activated with IL-33. LA reduced IL-33-mediated cytokine and chemokine production. Using inhibitors for monocarboxylate transporters (MCT) or replacing LA with sodium lactate revealed that LA effects are MCT-1- and pH-dependent. LA selectively altered IL-33 signaling, suppressing TGF-β-activated kinase-1, JNK, ERK, and NF-κB phosphorylation, but not p38 phosphorylation. LA effects in other contexts have been linked to hypoxia-inducible factor (HIF)-1α, which was enhanced in bone marrow-derived mast cells treated with LA. Because HIF-1α has been shown to regulate the microRNA miR-155 in other systems, LA effects on miR-155-5p and miR-155-3p species were measured. In fact, LA selectively suppressed miR-155-5p in an HIF-1α-dependent manner. Moreover, overexpressing miR-155-5p, but not miR-155-3p, abolished LA effects on IL-33-induced cytokine production. These in vitro effects of reducing cytokines were consistent in vivo, because LA injected i.p. into C57BL/6 mice suppressed IL-33-induced plasma cytokine levels. Lastly, IL-33 effects on primary human mast cells were suppressed by LA in an MCT-dependent manner. Our data demonstrate that LA, present in inflammatory and malignant microenvironments, can alter mast cell behavior to suppress inflammation.
authors: Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA 23284;
authors: Daniel
authors: 0000-0002-6837-3028
authors: D
authors: Abebayehu
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Andrew J
authors: AJ
authors: Spence
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Amina Abdul
authors: AA
authors: Qayum
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Marcela T
authors: MT
authors: Taruselli
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Jamie J A
authors: JJ
authors: McLeod
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Heather L
authors: HL
authors: Caslin
authors: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208; and.
authors: Alena P
authors: AP
authors: Chumanevich
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Elizabeth Motunrayo
authors: EM
authors: Kolawole
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Anuya
authors: A
authors: Paranjape
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Bianca
authors: B
authors: Baker
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Victor S
authors: VS
authors: Ndaw
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284;
authors: Brian O
authors: BO
authors: Barnstein
authors: Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC 29208; and.
authors: Carole A
authors: 0000-0003-1380-9186
authors: CA
authors: Oskeritzian
authors: Department of Biomedical Engineering, Saint Louis University, St. Louis, MO 63103.
authors: Scott A
authors: SA
authors: Sell
authors: Department of Biology, Virginia Commonwealth University, Richmond, VA 23284; jjryan@vcu.edu.
authors: John J
authors: JJ
authors: Ryan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000517:prevention & control*; D000067596:Interleukin-33 / Q000276:immunology*; D019344:Lactic Acid / Q000494:pharmacology*; D008297:Male; D008407:Mast Cells / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C506535:Il33 protein, mouse; D000067596:Interleukin-33; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D019344:Lactic Acid