Front Immunol 10: 2530

Mucosal Immunity and the FOXO1 Transcription Factors

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States

Edited by: Avi-Hai Hovav, Hebrew University of Jerusalem, Israel

Reviewed by: Richard Lamont, University of Louisville, United States; Nicolas Dutzan, University of Chile, Chile

*Correspondence: Dana T. Graves ude.nnepu@sevargtd

This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology

Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States

Edited by: Avi-Hai Hovav, Hebrew University of Jerusalem, Israel

Reviewed by: Richard Lamont, University of Louisville, United States; Nicolas Dutzan, University of Chile, Chile

Received 2018 Jun 25; Accepted 2019 Oct 11.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

FOXO1 transcription factors affect a number of cell types that are important in the host response. Cell types whose functions are modulated by FOXO1 include keratinocytes in the skin and mucosal dermis, neutrophils and macrophages, dendritic cells, Tregs and B-cells. FOXO1 is activated by bacterial or cytokine stimulation. Its translocation to the nucleus and binding to promoter regions of genes that have FOXO response elements is stimulated by the MAP kinase pathway and inhibited by the PI3 kinase/AKT pathway. Downstream gene targets of FOXO1 include pro-inflammatory signaling molecules (TLR2, TLR4, IL-1β, and TNF-α), wound healing factors (TGF-β, VEGF, and CTGF) adhesion molecules (integrins-β1, -β3, -β6, α_vβ₃, CD11b, CD18, and ICAM-1), chemokine receptors (CCR7 and CXCR2), B cell regulators (APRIL and BLYS), T-regulatory modulators (Foxp3 and CTLA-4), antioxidants (GPX-2 and cytoglobin), and DNA repair enzymes (GADD45α). Each of the above cell types are found in oral mucosa and modulated by bacteria or an inflammatory microenvironment. FOXO1 contributes to the regulation of these cells, which collectively maintain and repair the epithelial barrier, formation and activation of Tregs that are needed to resolve inflammation, mobilization, infiltration, and activation of anti-bacterial defenses in neutrophils, and the homing of dendritic cells to lymph nodes to induce T-cell and B-cell responses. The goal of the manuscript is to review how the transcription factor, FOXO1, contributes to the activation and regulation of key leukocytes needed to maintain homeostasis and respond to bacterial challenge in oral mucosal tissues. Examples are given with an emphasis on lineage specific deletion of Foxo1 to explore the impact of FOXO1 on cell behavior, inflammation and susceptibility to infection.

Keywords: bacteria, bone loss, forkhead, gingiva, immune, mucosa, periodontal disease, periodontitis

Abstract

Forkhead box-O (FOXO) transcription factors were first identified in Drosophila melanogaster (1). There are four members of this family in mammals, three of which (FOXO1, FOXO3, and FOXO4) have conserved sequence homologies while FOXO6 is more distantly related (2). FOXO proteins regulate cell survival and apoptosis, proliferation, energy metabolism, oxidative stress responses, and its mutations are closely linked to cancer formation (1, 3). FOXO1, FOXO3, and FOXO4 often have common target genes and function. However, there are differences that are related to interaction with different co-activators and co-repressors. For example, global Foxo1 deletion in mice is embryonically lethal in contrast to global ablation of Foxo3 or Foxo4, which is not. The biological functions of FOXOs can overlap but are not necessarily redundant. FOXOs act primarily as transcription factors following translocation to the nucleus but can sometimes have “off target” effects as co-regulators in the nucleus or by binding to other proteins in the cytoplasm (4).

FOXOs are controlled at several levels including expression, nuclear translocation, DNA binding and interaction with other proteins. FOXOs have four primary domains with the following functions: (a) DNA binding, (b) nuclear localization, (c) nuclear export, and (d) transactivation. FOXOs recognize two consensus response elements: a Daf-16 binding site (5′-GTAAA (T/C)AA) and an insulin-response element (5′-(C/A)(A/C)AAA(C/T)AA) (1). The core DNA sequence 5′-(A/C)AA(C/T)A is recognized by all FOXO-family members. FOXO post-translational modification involves acetylation, phosphorylation, ubiquitination, methylation, and glycosylation (1). The modifications affect nuclear translocation or exit from the nucleus, DNA binding, and interaction with co-repressors and co-activators (5). Kinases/phosphatases and acetylases/deacetylases modulate shuttling of FOXOs to and from the nucleus. FOXO1 nuclear localization and resulting transcriptional activity is downregulated by phosphorylation from insulin stimulation via the phosphoinositide-3-kinase/AKT pathway or conversely, up-regulated by phosphorylation at different aminoacids through RAS/mitogen-activated protein kinase activity (1). Deacetylation of FOXO1 typically enhances nuclear localization and activity while they are reduced by acetylation (6). Generally, the level of FOXO1 nuclear localization is proportional to its activity. However, we have found that high glucose increases FOXO1 nuclear localization but reduces induction of specific genes (TGF-β and VEGF) by reducing its binding to the promoter regions despite increased nuclear localization (7–10). In fact, FOXO1 can bind to specific molecules to act as part of a co-repressor or co-activator complex (11). In this regard it is not always simple to predict the impact of FOXO1 on a given activity since its function his highly modified by post-translational modification and interaction with other partners.

FOXOs play a key role in maintaining homeostasis and in adapting to environmental changes (2). Since FOXO1 is the best studied of the FOXO family it is the focus of this review. FOXO1 may have an important role in regulating several aspects of mucosal immunity by affecting dendritic cells (12), macrophage and neutrophil recruitment and activation (13–15), as well as T-helper cell and B-lymphocyte development and function (16–18). FoxO1 also affects immune responses by controlling cytokine production (19) and protecting hematopoietic stems cells from oxidative stress (20). In addition, FOXO1 regulates important aspects of keratinocyte function and potentially has a role in maintaining or repairing epithelial barrier function (21, 22). Surprisingly FOXO1 can have a specific effect under normal conditions and opposite effect in other conditions such those in diabetes and can have cell specific responses (21, 23). Thus, it is often difficult to predict the impact of FOXO1 and its role under various conditions. These studies demonstrate the complex nature of FOXO1 and its responsiveness to the cellular microenvironment, suggesting that it is highly regulated by epigenetic factors such as high glucose or those where oxidative stress is high. This is likely to be a fruitful area of future research.

Glossary

Abbreviations

FOXO 1	Forkhead box protein O1
TNF alpha	Tumor Necrosis factor alpha
TGF beta	transforming Growth factor
VEGF	Vascular Endothelial Growth factor
CTGF	Connective Tissue Growth Factor
APRIL	A-proliferation-inducing ligand
BLYS	B-lymphocyte Stimulator
ICAM-1	Intercellular Adhesion Molecule
GPX2	Glutathione peroxidase 2
GADD45a	Growth Arrest And DNA Damage Inducible Alpha
CCR7-C	C chemokine receptor type 7
Il-6	Interleukin 6
RANKL	Receptor activator of nuclear factor kappa-B ligand
DCs	Dendritic cells
Ly	Lymphocyte antigen
ROS	Reactive oxygen species
HO-1	Heme oxygenase 1
PD-L1	Programmed death-ligand 1
TLR	Toll like receptor
PDL-cells	periodontal ligament cells.

Glossary

Footnotes

Funding. This work was supported by NIH grants R01DE017732 and R01DE021921.

Footnotes

References

1. Wang Y, Zhou Y, Graves DT. FOXO transcription factors: their clinical significance and regulation. Biomed Res Int. (2014) 2014:925350. 10.1155/2014/925350 ] [
2. Tsuchiya K, Ogawa Y. Forkhead box class O family member proteins: the biology and pathophysiological roles in diabetes. J Diabetes Investig. (2017) 8:726–34. 10.1111/jdi.12651 ] [
3. Coomans deBrachene A, Demoulin JB. FOXO transcription factors in cancer development and therapy. Cell Mol Life Sci. (2016) 73:1159–72. 10.1007/s00018-015-2112-y [] [[PubMed][Google Scholar]
4. Iyer S, Ambrogini E, Bartell SM, Han L, Roberson PK, de Cabo R, et al. . FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest. (2013) 123:3409–19. 10.1172/JCI68049 ] [
5. Daitoku H, Sakamaki J, Fukamizu A. Regulation of FoxO transcription factors by acetylation and protein-protein interactions. Biochim Biophys Acta. (2011) 1813:1954–60. 10.1016/j.bbamcr.2011.03.001 [] [[PubMed]
6. Qiang L, Banks AS, Accili D. Uncoupling of acetylation from phosphorylation regulates FoxO1 function independent of its subcellular localization. J Biol Chem. (2010) 285:27396–401. 10.1074/jbc.M110.140228 ] [
7. Xu F, Othman B, Lim J, Batres A, Ponugoti B, Zhang C, et al. . Foxo1 inhibits diabetic mucosal wound healing but enhances healing of normoglycemic wounds. Diabetes. (2015) 64:243–56. 10.2337/db14-0589 ] [
8. Zhang C, Ponugoti B, Tian C, Xu F, Tarapore R, Batres A, et al. . FOXO1 differentially regulates both normal and diabetic wound healing. J Cell Biol. (2015) 209:289–303. 10.1083/jcb.201409032 ] [
9. Jeon HH, Yu Q, Lu Y, Spencer E, Lu C, Milovanova T, et al. . FOXO1 regulates VEGFA expression and promotes angiogenesis in healing wounds. J Pathol. (2018) 245:258–64. 10.1002/path.5075 ] [
10. Zhang C, Feinberg D, Alharbi M, Ding Z, Lu C, O'Connor JP, et al. . Chondrocytes promote vascularization in fracture healing through a FOXO1-dependent mechanism. J Bone Miner Res. (2019) 34:547–56. 10.1002/jbmr.3610 ] [
11. Jogdand GM, Mohanty S, Devadas S. Regulators of Tfh cell differentiation. Front Immunol. (2016) 7:520. 10.3389/fimmu.2016.00520 ] [
12. Dong G, Wang Y, Xiao W, Pacios Pujado S, Xu F, Tian C, et al. . FOXO1 regulates dendritic cell activity through ICAM-1 and CCR7. J Immunol. (2015) 194:3745–55. 10.4049/jimmunol.1401754 ] [
13. Chung S, Ranjan R, Lee YG, Park GY, Karpurapu M, Deng J, et al. . Distinct role of FoxO1 in M-CSF- and GM-CSF-differentiated macrophages contributes LPS-mediated IL-10: implication in hyperglycemia. J Leukoc Biol. (2015) 97:327–39. 10.1189/jlb.3A0514-251R ] [
14. Fan W, Morinaga H, Kim JJ, Bae E, Spann NJ, Heinz S, et al. . FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J. (2010) 29:4223–36. 10.1038/emboj.2010.268 ] [
15. Dong G, Song L, Tian C, Wang Y, Miao F, Zheng J, et al. . FOXO1 regulates bacteria-induced neutrophil activity. Front Immunol. (2017) 8:1088. 10.3389/fimmu.2017.01088 ] [
16. Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden KC, Castrillon DH, et al. . Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol. (2008) 9:1388–98. 10.1038/ni.1667 ] [
17. Kerdiles YM, Stone EL, Beisner DR, McGargill MA, Ch'en IL, Stockmann C, et al. . Foxo transcription factors control regulatory T cell development and function. Immunity. (2010) 33:890–904. 10.1016/j.immuni.2010.12.002 ] [
18. Yusuf I, Zhu X, Kharas MG, Chen J, Fruman DA. Optimal B-cell proliferation requires phosphoinositide 3-kinase-dependent inactivation of FOXO transcription factors. Blood. (2004) 104:784–7. 10.1182/blood-2003-09-3071 [] [[PubMed]
19. Behl Y, Siqueira M, Ortiz J, Li J, Desta T, Faibish D, et al. . Activation of the acquired immune response reduces coupled bone formation in response to a periodontal pathogen. J Immunol. (2008) 181:8711–8. 10.4049/jimmunol.181.12.8711 ] [
20. Ponugoti B, Dong G, Graves DT. Role of forkhead transcription factors in diabetes-induced oxidative stress. Exp Diabetes Res. (2012) 2012:939751. 10.1155/2012/939751 ] [
21. Xiao E, Graves DT. Impact of diabetes on the protective role of FOXO1 in wound healing. J Dent Res. (2015) 94:1025–6. 10.1177/0022034515586353 ] [
22. Tsitsipatis D, Klotz LO, Steinbrenner H. Multifaceted functions of the forkhead box transcription factors FoxO1 and FoxO3 in skin. Biochim Biophys Acta. (2017) 1861:1057–64. 10.1016/j.bbagen.2017.02.027 [] [[PubMed]
23. Eijkelenboom A, Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. (2013) 14:83–97. 10.1038/nrm3507 [] [[PubMed]
24. Graves DT, Li J, Cochran DL. Inflammation and uncoupling as mechanisms of periodontal bone loss. J Dent Res. (2011) 90:143–53. 10.1177/0022034510385236 ] [
25. Alvarez C, Monasterio G, Cavalla F, Córdova LA, Hernández M, Heymann D, et al Osteoimmunology of oral and maxillofacial diseases: translational applications based on biological mechanisms. Front Immunol. (2019) 18:166426 10.3389/fimmu.2019.01664 ] [[Google Scholar]
26. Beck JD, Papapanou PN, Philips KH, Offenbacher S. Periodontal medicine: 100 years of progress. J Dent Res. (2019) 98:1053–62. 10.1177/0022034519846113 [] [[PubMed]
27. Chukkapalli SS, Velsko IM, Rivera-Kweh MF, Larjava H, Lucas AR, Kesavalu L. Global TLR2 and 4 deficiency in mice impacts bone resorption, inflammatory markers and atherosclerosis to polymicrobial infection. Mol Oral Microbiol. (2017) 32:211–25. 10.1111/omi.12165 ] [
28. Sanavi F, Listgarten MA, Boyd F, Sallay K, Nowotny A. The colonization and establishment of invading bacteria in periodontium of ligature-treated immunosuppressed rats. J Periodontol. (1985) 56:273–80. 10.1902/jop.1985.56.5.273 [] [[PubMed]
29. Liu R, Bal HS, Desta T, Behl Y, Graves DT. Tumor necrosis factor-alpha mediates diabetes-enhanced apoptosis of matrix-producing cells and impairs diabetic healing. Am J Pathol. (2006) 168:757–64. 10.2353/ajpath.2006.050907 ] [
30. Assuma R, Oates T, Cochran D, Amar S, Graves D. IL-1 and TNF antagonists inhibit the inflammatory response and bone loss in experimental periodontitis. J Immun. (1998) 160:403–9. [[PubMed]
31. Graves D, Delima A, Assuma R, Amar S, Oates T, Cochran D. Interleukin-1 and tumor necrosis factor antagonists inhibit the progression of inflammatory cell infiltration toward alveolar bone in experimental periodontitis. J Periodontol. (1998) 69:1419–25. 10.1902/jop.1998.69.12.1419 [] [[PubMed]
32. Pacios S, Xiao W, Mattos M, Lim J, Tarapore RS, Alsadun S, et al. . Osteoblast lineage cells play an essential role in periodontal bone loss through activation of nuclear factor-kappa B. Sci Rep. (2015) 5:16694. 10.1038/srep16694 ] [
33. Zheng J, Chen S, Albiero ML, Vieira GHA, Wang J, Feng JQ, et al. . Diabetes activates periodontal ligament fibroblasts via NF-kappaB. In vivo J Dent Res. (2018) 97:580–8. 10.1177/0022034518755697 ] [
34. Xiao E, Mattos M, Vieira GHA, Chen S, Correa JD, Wu Y, et al. . Diabetes enhances IL-17 expression and alters the oral microbiome to increase its pathogenicity. Cell Host Microbe. (2017) 22:120–8 e124. 10.1016/j.chom.2017.06.014 ] [
35. Baek KJ, Ji S, Kim YC, Choi Y. Association of the invasion ability of Porphyromonas gingivalis with the severity of periodontitis. Virulence. (2015) 6:274–81. 10.1080/21505594.2014.1000764 ] [
36. Hajishengallis G, Korostoff JM. Revisiting the Page & Schroeder model: the good, the bad and the unknowns in the periodontal host response 40 years later. Periodontol 2000. (2017) 75:116–51. 10.1111/prd.12181 ] [
37. Van Dyke TE. Pro-resolving mediators in the regulation of periodontal disease. Mol Aspects Med. (2017) 58:21–36. 10.1016/j.mam.2017.04.006 ] [
38. Song L, Dong G, Guo L, Graves DT. The function of dendritic cells in modulating the host response. Mol Oral Microbiol. (2018) 33:13–21. 10.1111/omi.12195 ] [
39. Xiao W, Li S, Pacios S, Wang Y, Graves DT. Bone remodeling under pathological conditions. Front Oral Biol. (2016) 18:17–27. 10.1159/000351896 [] [[PubMed]
40. Griffen AL, Beall CJ, Campbell JH, Firestone ND, Kumar PS, Yang ZK, et al. . Distinct and complex bacterial profiles in human periodontitis and health revealed by 16S pyrosequencing. ISME J. (2012) 6:1176–85. 10.1038/ismej.2011.191 ] [
41. Abusleme L, Dupuy AK, Dutzan N, Silva N, Burleson JA, Strausbaugh LD, et al. . The subgingival microbiome in health and periodontitis and its relationship with community biomass and inflammation. ISME J. (2013) 7:1016–25. 10.1038/ismej.2012.174 ] [
42. de Vries TJ, Andreotta S, Loos BG, Nicu EA. Genes critical for developing periodontitis: lessons from mouse models. Front Immunol.8:1395. 10.3389/fimmu.2017.01395 ] [
43. Kimball JR, Nittayananta W, Klausner M, Chung WO, Dale BA. Antimicrobial barrier of an in vitro oral epithelial model. Arch Oral Biol. (2006) 51:775–83. 10.1016/j.archoralbio.2006.05.007 ] [
44. Fujita T, Yoshimoto T, Kajiya M, Ouhara K, Matsuda S, Takemura T, et al. . Regulation of defensive function on gingival epithelial cells can prevent periodontal disease. Jpn Dent Sci Rev. (2018) 54:66–75. 10.1016/j.jdsr.2017.11.003 ] [
45. Dickinson BC, Moffatt CE, Hagerty D, Whitmore SE, Brown TA, Graves DT, et al. . Interaction of oral bacteria with gingival epithelial cell multilayers. Mol Oral Microbiol. (2011) 26:210–20. 10.1111/j.2041-1014.2011.00609.x ] [
46. Hameedaldeen A, Liu J, Batres A, Graves GS, Graves DT. FOXO1, TGF-beta regulation and wound healing. Int J Mol Sci. (2014) 15:16257–69. 10.3390/ijms150916257 ] [
47. Li S, Dong G, Moschidis A, Ortiz J, Benakanakere MR, Kinane DF, et al. . P. gingivalis modulates keratinocytes through FOXO transcription factors. PLoS ONE. (2013) 8:e78541. 10.1371/journal.pone.0078541 ] [
48. Wang Q, Sztukowska M, Ojo A, Scott DA, Wang H, Lamont RJ. FOXO responses to Porphyromonas gingivalis in epithelial cells. Cell Microbiol. (2015) 17:1605–17. 10.1111/cmi.12459 ] [
49. Ponugoti B, Xu F, Zhang C, Tian C, Pacios S, Graves DT. FOXO1 promotes wound healing through the up-regulation of TGF-beta1 and prevention of oxidative stress. J Cell Biol. (2013) 203:327–43. 10.1083/jcb.201305074 ] [
50. Gomis RR, Alarcon C, He W, Wang Q, Seoane J, Lash A, et al. . A FoxO-Smad synexpression group in human keratinocytes. Proc Natl Acad Sci USA. (2006) 103:12747–52. 10.1073/pnas.0605333103 ] [
51. Zhang C, Lim J, Liu J, Ponugoti B, Alsadun S, Tian C, et al. . FOXO1 expression in keratinocytes promotes connective tissue healing. Sci Rep. (2017) 7:42834. 10.1038/srep42834 ] [
52. Gaddis DE, Michalek SM, Katz J. Requirement of TLR4 and CD14 in dendritic cell activation by Hemagglutinin B from Porphyromonas gingivalis. Mol Immunol. (2009) 46:2493–504. 10.1016/j.molimm.2009.05.022 ] [
53. Su H, Yan X, Dong Z, Chen W, Lin ZT, Hu QG. Differential roles of Porphyromonas gingivalis lipopolysaccharide and Escherichia coli lipopolysaccharide in maturation and antigen-presenting functions of dentritic cells. Eur Rev Med Pharmacol Sci. (2015) 19:2482–92. [[PubMed]
54. Berggreen E, Wiig H. Lymphangiogenesis and lymphatic function in periodontal disease. J Dent Res. (2013) 92:1074–80. 10.1177/0022034513504589 [] [[PubMed]
55. Moughal NA, Adonogianaki E, Kinane DF. Langerhans cell dynamics in human gingiva during experimentally induced inflammation. J Biol Buccale. (1992) 20:163–7. [[PubMed]
56. Dereka XE, Tosios KI, Chrysomali E, Angelopoulou E. Factor XIIIa+ dendritic cells and S-100 protein+ Langerhans' cells in adult periodontitis. J Periodont Res. (2004) 39:447–52. 10.1111/j.1600-0765.2004.00764.x [] [[PubMed]
57. Arizon M, Nudel I, Segev H, Mizraji G, Elnekave M, Furmanov K, et al. . Langerhans cells down-regulate inflammation-driven alveolar bone loss. Proc Natl Acad Sci USA. (2012) 109:7043–8. 10.1073/pnas.1116770109 ] [
58. Bittner-Eddy PD, Fischer LA, Kaplan DH, Thieu K, Costalonga M. Mucosal langerhans cells promote differentiation of Th17 cells in a murine model of periodontitis but are not required for Porphyromonas gingivalis-driven alveolar bone destruction. J Immunol. (2016) 197:1435–46. 10.4049/jimmunol.1502693 ] [
59. Xiao W, Dong G, Pacios S, Alnammary M, Barger LA, Wang Y, et al. . FOXO1 deletion reduces dendritic cell function and enhances susceptibility to periodontitis. Am J Pathol. (2015) 185:1085–93. 10.1016/j.ajpath.2014.12.006 ] [
60. Brown J, Wang H, Suttles J, Graves DT, Martin M. Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1. J Biol Chem. (2011) 286:44295–305. 10.1074/jbc.M111.258053 ] [
61. Arjunan P, El-Awady A, Dannebaum RO, Kunde-Ramamoorthy G, Cutler CW. High-throughput sequencing reveals key genes and immune homeostatic pathways activated in myeloid dendritic cells by Porphyromonas gingivalis 381 and its fimbrial mutants. Mol Oral Microbiol. (2016) 31:78–93. 10.1111/omi.12131 ] [
62. Wu Y, Dong G, Xiao W, Xiao E, Miao F, Syverson A, et al. . Effect of aging on periodontal inflammation, microbial colonization, and disease susceptibility. J Dent Res. (2016) 95:460–6. 10.1177/0022034515625962 ] [
63. Zaal A, Nota B, Moore KS, Dieker M, van Ham SM, Ten Brinke A. TLR4 and C5aR crosstalk in dendritic cells induces a core regulatory network of RSK2, PI3Kbeta, SGK1, and FOXO transcription factors. J Leukoc Biol. (2017) 102:1035–54. 10.1189/jlb.2MA0217-058R [] [[PubMed]
64. Weichhart T, Saemann MD. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis. (2008) 67(Suppl 3):iii70–4. 10.1136/ard.2008.098459 [] [[PubMed]
65. Wilensky A, Mizraji G, Tabib Y, Sharawi H, Hovav AH. Analysis of leukocytes in oral mucosal tissues. Methods Mol Biol. (2017) 1559:267–78. 10.1007/978-1-4939-6786-5_18 [] [[PubMed]
66. Engel D. Lymphocyte function in early-onset periodontitis. J Periodontol. (1996) 67(Suppl 3S):332–6. 10.1902/jop.1996.67.3s.332 [] [[PubMed]
67. Araujo-Pires AC, Vieira AE, Francisconi CF, Biguetti CC, Glowacki A, Yoshizawa S, et al. . IL-4/CCL22/CCR4 axis controls regulatory T-cell migration that suppresses inflammatory bone loss in murine experimental periodontitis. J Bone Miner Res. (2015) 30:412–22. 10.1002/jbmr.2376 ] [
68. Chen XT, Chen LL, Tan JY, Shi DH, Ke T, Lei LH. Th17 and Th1 lymphocytes are correlated with chronic periodontitis. Immunol Invest. (2016) 45:243–54. 10.3109/08820139.2016.1138967 [] [[PubMed]
69. Francisconi CF, Vieira AE, Azevedo MCS, Tabanez AP, Fonseca AC, Trombone APF, et al. . RANKL triggers Treg-mediated immunoregulation in inflammatory osteolysis. J Dent Res. (2018) 97:917–27. 10.1177/0022034518759302 ] [
70. Ouyang W, Liao W, Luo CT, Yin N, Huse M, Kim MV, et al. . Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. (2012) 491:554–9. 10.1038/nature11581 ] [
71. Bothur E, Raifer H, Haftmann C, Stittrich AB, Brustle A, Brenner D, et al. . Antigen receptor-mediated depletion of FOXP3 in induced regulatory T-lymphocytes via PTPN2 and FOXO1. Nat Commun. (2015) 6:8576. 10.1038/ncomms9576 ] [
72. Hawse WF, Sheehan RP, Miskov-Zivanov N, Menk AV, Kane LP, Faeder JR, et al. . Cutting edge: differential regulation of PTEN by TCR, Akt, and FoxO1 controls CD4^{T cell fate decisions}. J Immunol. (2015) 194:4615–9. 10.4049/jimmunol.1402554 ] [
73. Dominguez-Sola D, Kung J, Holmes AB, Wells VA, Mo T, Basso K, et al. . The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity. (2015) 43:1064–74. 10.1016/j.immuni.2015.10.015 [] [[PubMed]
74. Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA. Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity. (2012) 36:374–87. 10.1016/j.immuni.2012.01.015 ] [
75. Harada Y, Harada Y, Elly C, Ying G, Paik JH, DePinho RA, et al. . Transcription factors Foxo3a and Foxo1 couple the E3 ligase Cbl-b to the induction of Foxp3 expression in induced regulatory T cells. J Exp Med. (2010) 207:1381–91. 10.1084/jem.20100004 ] [
76. Clarke EV, Tenner AJ. Complement modulation of T cell immune responses during homeostasis and disease. J Leukoc Biol. (2014) 96:745–56. 10.1189/jlb.3MR0214-109R ] [
77. Malyshev I, Malyshev Y. Current concept and update of the macrophage plasticity concept: intracellular mechanisms of reprogramming and M3 macrophage switch phenotype. Biomed Res Int. (2015) 2015:341308. 10.1155/2015/341308 ] [
78. Salvi GE, Brown CE, Fujihashi K, Kiyono H, Smith FW, Beck JD, et al. . Inflammatory mediators of the terminal dentition in adult and early onset periodontitis. J Periodont Res. (1998) 33:212–25. 10.1111/j.1600-0765.1998.tb02193.x [] [[PubMed]
79. Wang YC, Ma HD, Yin XY, Wang YH, Liu QZ, Yang JB, et al. . Forkhead box O1 regulates macrophage polarization following staphylococcus aureus infection: experimental murine data and review of the literature. Clin Rev Allergy Immunol. (2016) 51:353–69. 10.1007/s12016-016-8531-1 [] [[PubMed]
80. Miao H, Ou J, Zhang X, Chen Y, Xue B, Shi H, et al. . Macrophage CGI-58 deficiency promotes IL-1beta transcription by activating the SOCS3-FOXO1 pathway. Clin Sci. (2015) 128:493–506. 10.1042/CS20140414 [] [[PubMed]
81. Tsuchiya K, Westerterp M, Murphy AJ, Subramanian V, Ferrante AW, Jr, Tall AR, et al. . Expanded granulocyte/monocyte compartment in myeloid-specific triple FoxO knockout increases oxidative stress and accelerates atherosclerosis in mice. Circ Res. (2013) 112:992–1003. 10.1161/CIRCRESAHA.112.300749 ] [
82. Yang JB, Zhao ZB, Liu QZ, Hu TD, Long J, Yan K, et al. . FoxO1 is a regulator of MHC-II expression and anti-tumor effect of tumor-associated macrophages. Oncogene. (2018) 37:1192–204. 10.1038/s41388-017-0048-4 [] [[PubMed]
83. Liu X, Wang N, Zhu Y, Yang Y, Chen X, Chen Q, et al. . Extracellular calcium influx promotes antibacterial autophagy in Escherichia coli infected murine macrophages via CaMKKbeta dependent activation of ERK1/2, AMPK and FoxO1. Biochem Biophys Res Commun. (2016) 469:639–45. 10.1016/j.bbrc.2015.12.052 [] [[PubMed]
84. Jati S, Kundu S, Chakraborty A, Mahata SK, Nizet V, Sen M. Wnt5A signaling promotes defense against bacterial pathogens by activating a host autophagy circuit. Front Immunol. (2018) 9:679. 10.3389/fimmu.2018.00679 ] [
85. Herrmann JM, Meyle J. Neutrophil activation and periodontal tissue injury. Periodontol 2000. (2015) 69:111–27. 10.1111/prd.12088 [] [[PubMed]
86. Mark Bartold P, Van Dyke TE. Host modulation: controlling the inflammation to control the infection. Periodontol 2000. (2017) 75:317–29. 10.1111/prd.12169 [] [[PubMed]
87. Wang J, Arase H. Regulation of immune responses by neutrophils. Ann N Y Acad Sci. (2014) 1319:66–81. 10.1111/nyas.12445 [] [[PubMed]