PMID- 35032412 OWN - NLM STAT- MEDLINE DCOM- 20220214 LR - 20230202 IS - 1530-6860 (Electronic) IS - 0892-6638 (Print) IS - 0892-6638 (Linking) VI - 36 IP - 2 DP - 2022 Feb TI - Decoding the role of macrophages in periodontitis and type 2 diabetes using single-cell RNA-sequencing. PG - e22136 LID - 10.1096/fj.202101198R [doi] AB - Macrophages are resident myeloid cells in the gingival tissue which control homeostasis and play a pivotal role in orchestrating the immune response in periodontitis. Cell heterogeneity and functional phenotypes of macrophage subpopulations in periodontitis remain elusive. Here, we isolated gingival tissue from periodontitis-affected and healthy sites of patients with and without type 2 diabetes mellitus (T2DM). We then used single-cell RNA-sequencing (scRNA-seq) to define the heterogeneity of tissue-resident macrophages in gingival tissue in health vs. periodontitis. scRNA-seq demonstrated an unforeseen gene expression heterogeneity among macrophages in periodontitis and showed transcriptional and signaling heterogeneity of identified subsets in an independent cohort of patients with periodontitis and T2DM. Our bioinformatic inferences indicated divergent expression profiles in macrophages driven by transcriptional regulators CIITA, RELA, RFX5, and RUNX2. Macrophages in periodontitis expressed both pro-inflammatory and anti-inflammatory markers and their polarization was not mutually exclusive. The majority of macrophages in periodontitis expressed the monocyte lineage marker CD14, indicating their bone marrow lineage. We also found high expression and activation of RELA, a subunit of the NF-kappaB transcription factor complex, in gingival macrophages of periodontitis patients with T2DM. Our data suggested that heterogeneity and hyperinflammatory activation of macrophages may be relevant to the pathogenesis and outcomes of periodontitis, and may be further augmented in patients with T2DM. CI - (c) 2022 Federation of American Societies for Experimental Biology. FAU - Agrafioti, Panagiota AU - Agrafioti P AD - Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA. AD - Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA. FAU - Morin-Baxter, Joshua AU - Morin-Baxter J AD - Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA. AD - Fu Foundation School of Engineering and Applied Science, Columbia University, New York, New York, USA. FAU - Tanagala, Kranthi K K AU - Tanagala KKK AD - Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA. AD - Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA. FAU - Dubey, Sunil AU - Dubey S AD - Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA. AD - Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA. FAU - Sims, Peter AU - Sims P AD - Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA. AD - Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, New York, USA. FAU - Lalla, Evanthia AU - Lalla E AD - Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA. FAU - Momen-Heravi, Fatemeh AU - Momen-Heravi F AUID- ORCID: 0000-0003-4534-1450 AD - Division of Periodontics, Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York, USA. AD - Cancer Biology and Immunology Laboratory, Columbia University Irving Medical Center, New York, New York, USA. AD - Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York, USA. LA - eng GR - KL2 TR001874/TR/NCATS NIH HHS/United States GR - L30 DE029070/DE/NIDCR NIH HHS/United States GR - R03 DE029546/DE/NIDCR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - FASEB J JT - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JID - 8804484 RN - 0 (Biomarkers) RN - 0 (Lipopolysaccharide Receptors) RN - 0 (Transcription Factors) RN - 63231-63-0 (RNA) SB - IM MH - Aged MH - Biomarkers/metabolism MH - Bone Marrow/metabolism MH - Cell Lineage/genetics MH - Diabetes Mellitus, Type 2/*genetics/*metabolism MH - Female MH - Gingiva/metabolism MH - Humans MH - Inflammation/genetics/metabolism MH - Lipopolysaccharide Receptors/genetics MH - Macrophages/*metabolism MH - Male MH - Middle Aged MH - Monocytes/metabolism MH - Myeloid Cells/metabolism MH - Periodontitis/*genetics/*metabolism MH - RNA/*genetics MH - Sequence Analysis, RNA/methods MH - Signal Transduction/genetics MH - Transcription Factors/genetics MH - Transcription, Genetic/genetics MH - Transcriptome/genetics PMC - PMC8881186 MID - NIHMS1765711 OTO - NOTNLM OT - macrophages OT - periodontitis OT - single-cell RNA-sequencing OT - type 2 diabetes COIS- DISCLOSURES The authors declare that they have no competing interests. EDAT- 2022/01/16 06:00 MHDA- 2022/02/15 06:00 PMCR- 2023/02/01 CRDT- 2022/01/15 17:05 PHST- 2021/11/14 00:00 [revised] PHST- 2021/07/27 00:00 [received] PHST- 2021/12/17 00:00 [accepted] PHST- 2022/01/15 17:05 [entrez] PHST- 2022/01/16 06:00 [pubmed] PHST- 2022/02/15 06:00 [medline] PHST- 2023/02/01 00:00 [pmc-release] AID - 10.1096/fj.202101198R [doi] PST - ppublish SO - FASEB J. 2022 Feb;36(2):e22136. doi: 10.1096/fj.202101198R.