PMID- 36121152 OWN - NLM STAT- MEDLINE DCOM- 20221028 LR - 20221128 IS - 2150-7511 (Electronic) VI - 13 IP - 5 DP - 2022 Oct 26 TI - High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages. PG - e0108622 LID - 10.1128/mbio.01086-22 [doi] LID - e01086-22 AB - Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), but the mechanisms behind diabetes-TB comorbidity are still undefined. Here, we studied the role of hypoxia-inducible factor-1 (HIF-1), a main regulator of metabolic and inflammatory responses, in the outcome of Mycobacterium tuberculosis infection of bone marrow-derived macrophages (BMM). We observed that M. tuberculosis infection of BMM increased the expression of HIF-1alpha and HIF-1-regulated genes. Treatment with the hypoxia mimetic deferoxamine (DFO) further increased levels of HIF-1-regulated immune and metabolic molecules and diminished the intracellular bacterial load in BMM and in the lungs of infected mice. The expression of HIF-1-regulated immunometabolic genes was reduced, and the intracellular M. tuberculosis levels were increased in BMM incubated with high-glucose levels or with methylglyoxal (MGO), a reactive carbonyl compound elevated in DM. In line with the in vitro findings, high M. tuberculosis levels and low HIF-1-regulated transcript levels were found in the lungs from hyperglycemic Lepr(db/db) compared with wild-type mice. The increased intracellular M. tuberculosis growth and the reduced expression of HIF-1-regulated metabolic and inflammatory genes in BMM incubated with MGO or high glucose were reverted by additional treatment with DFO. Hif1a-deficient BMM showed ablated responses of immunometabolic transcripts after mycobacterial infection at normal or high-glucose levels. We propose that HIF-1 may be targeted for the control of M. tuberculosis during DM. IMPORTANCE People living with diabetes who are also infected with M. tuberculosis are more likely to develop tuberculosis disease (TB). Why diabetic patients have an increased risk for developing TB is not well understood. Macrophages, the cell niche for M. tuberculosis, can express microbicidal mechanisms or be permissive to mycobacterial persistence and growth. Here, we showed that high glucose and carbonyl stress, which mediate diabetes pathogenesis, impair the control of intracellular M. tuberculosis in macrophages. Infection with M. tuberculosis stimulated the expression of genes regulated by the transcription factor HIF-1, a major controller of the responses to hypoxia, resulting in macrophage activation. High glucose and carbonyl compounds inhibited HIF-1 responses by macrophages. Mycobacterial control in the presence of glucose or carbonyl stress was restored by DFO, a compound that stabilizes HIF-1. We propose that HIF-1 can be targeted to reduce the risk of developing TB in people with diabetes. FAU - Teran, Graciela AU - Teran G AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. FAU - Li, Hanxiong AU - Li H AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. FAU - Catrina, Sergiu-Bogdan AU - Catrina SB AD - Department of Molecular Medicine and Surgery, Karolinska Institutegrid.4714.6t, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, Stockholm, Sweden. AD - Center for Diabetes, Academic Specialist Center, Stockholm, Sweden. FAU - Liu, Ruining AU - Liu R AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. FAU - Brighenti, Susanna AU - Brighenti S AD - Center for Infectious Medicine (CIM), Department of Medicine, Karolinska Institutegrid.4714.6t, Stockholm, Sweden. FAU - Zheng, Xiaowei AU - Zheng X AD - Department of Molecular Medicine and Surgery, Karolinska Institutegrid.4714.6t, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, Stockholm, Sweden. FAU - Grunler, Jakob AU - Grunler J AD - Department of Molecular Medicine and Surgery, Karolinska Institutegrid.4714.6t, Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska University Hospital, Stockholm, Sweden. FAU - Nylen, Susanne AU - Nylen S AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. FAU - Carow, Berit AU - Carow B AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. FAU - Rottenberg, Martin E AU - Rottenberg ME AUID- ORCID: 0000-0003-0514-7434 AD - Department of Microbiology, Tumor and Cell Biology (MTC), Karolinska Institutegrid.4714.6t, Stockholm Sweden. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20220919 PL - United States TA - mBio JT - mBio JID - 101519231 RN - 0 (Hypoxia-Inducible Factor 1) RN - 722KLD7415 (Pyruvaldehyde) RN - J06Y7MXW4D (Deferoxamine) RN - 3A3U0GI71G (Magnesium Oxide) RN - IY9XDZ35W2 (Glucose) SB - IM MH - Mice MH - Animals MH - *Mycobacterium tuberculosis/physiology MH - Hypoxia-Inducible Factor 1/metabolism MH - Pyruvaldehyde/metabolism MH - Deferoxamine/pharmacology/metabolism MH - Magnesium Oxide/metabolism MH - *Tuberculosis/microbiology MH - Macrophages/microbiology MH - Hypoxia/metabolism MH - Glucose/metabolism PMC - PMC9600926 OTO - NOTNLM OT - HIF-1 OT - Mycobacterium tuberculosis OT - diabetes OT - macrophage COIS- The authors declare no conflict of interest. EDAT- 2022/09/20 06:00 MHDA- 2022/10/29 06:00 PMCR- 2022/09/19 CRDT- 2022/09/19 08:02 PHST- 2022/09/20 06:00 [pubmed] PHST- 2022/10/29 06:00 [medline] PHST- 2022/09/19 08:02 [entrez] PHST- 2022/09/19 00:00 [pmc-release] AID - 01086-22 [pii] AID - mbio.01086-22 [pii] AID - 10.1128/mbio.01086-22 [doi] PST - ppublish SO - mBio. 2022 Oct 26;13(5):e0108622. doi: 10.1128/mbio.01086-22. Epub 2022 Sep 19.