Sex-specific regulation of immune responses by PPARs

다국어 초록 (Multilingual Abstract)

The prevalence of autoimmune, infectious and metabolic diseases is different for men and women owing to the respective ability of their immune systems to respond to self and foreign antigens. Although several factors, including hormones and the X-chromosome, have been suggested to contribute to such sex-specific immune responses, the underlying factors remain poorly defined. Recent studies using peroxisome proliferator-activated receptor (PPAR) ligands and knockout mice have identified sex-dimorphic expression of PPARs, and have shown that the inhibitory functions of PPAR in T cells are substantially affected by the sex hormones. In this review, we consider the sex-specific differences in PPARs and summarize the diverse PPAR-mediated, sex-specific properties of effector T-cell responses, such as T-cell activation, survival and differentiation, as well as their involvement in T-cell-related autoimmune diseases, including colitis, graft-versus-host disease and experimental autoimmune encephalomyelitis. Understanding PPAR-mediated sex differences in immune responses will provide more precise insights into the roles of PPARs in effector T cells.

참고문헌 (Reference)

1 Pinheiro I, "X-chromosome-located microRNAs in immunity: might they explain male/female differences? The X chromosome-genomic context may affect X-located miRNAs and downstream signaling, thereby contributing to the enhanced immune response of females" 33 : 791-802, 2011

2 Laffont S, "X-chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-α production of plasmacytoid dendritic cells from women" 193 : 5444-5452, 2014

3 Fairweather D, "Women and autoimmune diseases" 10 : 2005-2011, 2004

4 Gocke AR, "Transcriptional modulation of the immune response by peroxisome proliferator-activated receptor-{alpha} agonists in autoimmune disease" 182 : 4479-4487, 2009

5 Auboeuf D, "Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans : no alteration in adipose tissue of obese and NIDDM patients" 46 : 1319-1327, 1997

6 Clark RB, "The role of PPARs in inflammation and immunity" 71 : 388-400, 2002

7 Ricote M, "The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation" 391 : 79-82, 1998

8 Fajas L, "The organization, promoter analysis, and expression of the human PPARgamma gene" 272 : 18779-18789, 1997

9 Chen X, "The number of x chromosomes causes sex differences in adiposity in mice" 8 : e1002709-, 2012

10 Klotz L, "The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity" 206 : 2079-2089, 2009

11 Clark RB, "The nuclear receptor PPAR and immunoregulation : PPAR mediates inhibition of helper T cell responses" 164 : 1364-1371, 2000

12 Oertelt-Prigione S, "The influence of sex and gender on the immune response" 11 : A479-A485, 2012

13 Golden LC, "The importance of studying sex differences in disease : The example of multiple sclerosis" 95 : 633-643, 2017

14 Malkin CJ, "The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men" 89 : 3313-3318, 2004

15 Straub RH, "The complex role of estrogens in inflammation" 28 : 521-574, 2007

16 Klein SL, "The Xs and Y of immune responses to viral vaccines" 10 : 338-349, 2010

17 Libert C, "The X chromosome in immune functions : when a chromosome makes the difference" 10 : 594-604, 2010

18 최제민, "The Nuclear Receptor PPARs as Important Regulators of T-Cell Functions and Autoimmune Diseases" 한국분자세포생물학회 33 (33): 217-222, 2012

19 Rettew JA, "Testosterone reduces macrophage expression in the mouse of toll-like receptor 4, a trigger for inflammation and innate immunity" 78 : 432-437, 2008

20 Liva SM, "Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production" 167 : 2060-2067, 2001

21 Berghöfer B, "TLR7ligands induce higher IFN-alpha production in females" 177 : 2088-2096, 2006

22 Lisse IM, "T-lymphocyte subsets in West African children: impact of age, sex, and season" 130 : 77-85, 1997

23 Furman D, "Systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination" 111 : 869-874, 2014

24 Hewagama A, "Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis" 10 : 509-516, 2009

25 Tontonoz P, "Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor" 79 : 1147-1156, 1994

26 Moxley G, "Sexual dimorphism in innate immunity" 46 : 250-258, 2002

27 Furman D, "Sexual dimorphism in immunity : improving our understanding of vaccine immune responses in men" 14 : 461-471, 2015

28 Marriott I, "Sexual dimorphism in expression of receptors for bacterial lipopolysaccharides in murine macrophages : a possible mechanism for gender-based differences in endotoxic shock susceptibility" 71 : 12-27, 2006

29 Park HJ, "Sex-based selectivity of PPARγ regulation in Th1, Th2, and Th17 Differentiation" 17 : 1347-, 2016

30 Roberts CW, "Sex-associated hormones and immunity to protozoan parasites" 14 : 476-488, 2001

31 Bouman A, "Sex hormones and the immune response in humans" 11 : 411-423, 2005

32 Sankaran-Walters S, "Sex differences matter in the gut : effect on mucosal immune activation and inflammation" 4 : 10-, 2013

33 Torcia MG, "Sex differences in the response to viral infections: TLR8 and TLR9ligand stimulation induce higher IL10 production in males" 7 : e39853-, 2012

34 Hannah MF, "Sex differences in the recognition of and innate antiviral responses to Seoul virus in Norway rats" 22 : 503-516, 2008

35 Markle JG, "Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity" 339 : 1084-1088, 2013

36 Dai R, "Sex differences in the expression of lupus-associated miRNAs in splenocytes from lupus-prone NZB/WF1 mice" 4 : 19-, 2013

37 Kawai K, "Sex differences in the effects of maternal vitamin supplements on mortality and morbidity among children born to HIV-infected women in Tanzania" 103 : 1784-1791, 2010

38 Griesbeck M, "Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-α production in women" 195 : 5327-5336, 2015

39 Klein SL, "Sex differences in immune responses" 16 : 626-638, 2016

40 Maher AC, "Sex differences in global mRNA content of human skeletal muscle" 4 : e6335-, 2009

41 Papenfuss TL, "Sex differences in experimental autoimmune encephalomyelitis in multiple murine strains" 150 : 59-69, 2004

42 Voskuhl R, "Sex differences in autoimmune diseases" 2 : 1-, 2011

43 Fairweather D, "Sex differences in autoimmune disease from a pathological perspective" 173 : 600-609, 2008

44 Whitacre CC, "Sex differences in autoimmune disease" 2 : 777-780, 2001

45 Ciháková D, "Sex differences in a murine model of Sjögren’s syndrome" 1173 : 378-383, 2009

46 Ziegler S, "Sex differences in HIV-1-mediated immunopathology" 11 : 209-215, 2016

47 Robinson DP, "Sex chromosome complement contributes to sex differences in coxsackievirus B3 but not influenza A virus pathogenesis" 2 : 8-, 2011

48 Yki-Järvinen H, "Sex and insulin sensitivity" 33 : 1011-1015, 1984

49 Menzies FM, "Selective inhibition and augmentation of alternative macrophage activation by progesterone" 134 : 281-291, 2011

50 Patel J, "Rosiglitazone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study" 1 : 165-172, 1999

51 Hamm JK, "Role of PPAR gamma in regulating adipocyte differentiation and insulin-responsive glucose uptake" 892 : 134-145, 1999

52 Sinha A, "Reduced risk of neonatal respiratory infections among breastfed girls but not boys" 112 : e303-, 2003

53 Polak PE, "Protective effects of a peroxisome proliferator-activated receptor-beta/delta agonist in experimental autoimmune encephalomyelitis" 168 : 65-75, 2005

54 Klotz L, "Proinflammatory stimulation and pioglitazone treatment regulate peroxisome proliferator-activated receptor gamma levels in peripheral blood mononuclear cells from healthy controls and multiple sclerosis patients" 175 : 4948-4955, 2005

55 Butts CL, "Progesterone inhibits mature rat dendritic cells in a receptor-mediated fashion" 19 : 287-296, 2007

56 Wohlfert EA, "Peroxisome proliferatoractivated receptor gamma(PPARgamma)and immunoregulation : enhancement of regulatory T cells through PPARgamma-dependent and-independent mechanisms" 178 : 4129-4135, 2007

57 Tobiasova Z, "Peroxisome proliferator-activated receptor-gamma agonists prevent in vivo remodeling of human artery induced by alloreactive T cells" 124 : 196-205, 2011

58 Dunn SE, "Peroxisome proliferator-activated receptor(PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity" 204 : 321-330, 2007

59 Zhang MA, "Peroxisome proliferator-activated receptor(PPAR)alpha and-gamma regulate IFNgamma and IL-17A production by human T cells in a sex-specific way" 109 : 9505-9510, 2012

60 Hontecillas R, "Peroxisome proliferator-activated receptor is required for regulatory CD4+ T cell-mediated protection against colitis" 178 : 2940-2949, 2007

61 Jo SH, "Peroxisome proliferator-activated receptor gamma promotes lymphocyte survival through its actions on cellular metabolic activities" 177 : 3737-3745, 2006

62 Housley WJ, "Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity" 187 : 4161-4169, 2011

63 Dunn SE, "Peroxisome proliferator-activated receptor delta limits the expansion of pathogenic Th cells during central nervous system autoimmunity" 207 : 1599-1608, 2010

64 Lovett-Racke AE, "Peroxisome proliferator-activated receptor alpha agonists as therapy for autoimmune disease" 172 : 5790-5798, 2004

65 Kanakasabai S, "PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis" 1376 : 101-112, 2011

66 Park HJ, "PPARgamma negatively regulates T cell activation to prevent follicular helper T cells and germinal center formation" 9 : e99127-, 2014

67 Cipolletta D, "PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells" 486 : 549-553, 2012

68 Jiang C, "PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines" 391 : 82-86, 1998

69 Mukundan L, "PPAR-delta senses and orchestrates clearance of apoptotic cells to promote tolerance" 15 : 1266-1272, 2009

70 Jones DC, "Nuclear receptor peroxisome proliferatoractivated receptor alpha (PPARalpha) is expressed in resting murine lymphocytes. The PPARalpha in T and B lymphocytes is both transactivation and transrepression competent" 277 : 6838-6845, 2002

71 Uppal SS, "Normal values of CD4 and CD8 lymphocyte subsets in healthy Indian adults and the effects of sex, age, ethnicity, and smoking" 52 : 32-36, 2003

72 Bobjer J, "Negative association between testosterone concentration and inflammatory markers in young men: a nested cross-sectional study" 8 : e61466-, 2013

73 Dubrac S, "Lack of IL-2 in PPAR-α-deficient mice triggers allergic contact dermatitis by affecting regulatory T cells" 41 : 1980-1991, 2011

74 박홍재, "Insights into the Role of Follicular Helper T Cells in Autoimmunity" 대한면역학회 14 (14): 15-29, 2014

75 Sharma S, "Influence of sex differences on microRNA gene regulation in disease" 5 : 3-, 2014

76 Bolnick DI, "Individual diet has sex-dependent effects on vertebrate gut microbiota" 5 : 4500-, 2014

77 Engler RJ, "Half- vs full-dose trivalent inactivated influenza vaccine (2004–2005): age, dose, and sex effects on immune responses" 168 : 2405-2414, 2008

78 Bebo BF Jr, "Gonadal hormones influence the immune response to PLP 139-151 and the clinical course of relapsing experimental autoimmune encephalomyelitis" 84 : 122-130, 1998

79 Park HJ, "Gender-specific differences in PPARgamma regulation of follicular helper T cell responses with estrogen" 6 : 28495-, 2016

80 Abdullah M, "Gender effect on in vitro lymphocyte subset levels of healthy individuals" 272 : 214-219, 2012

81 Aomatsu M, "Gender difference in tumor necrosis factor-α production in human neutrophils stimulated by lipopolysaccharide and interferon-γ" 441 : 220-225, 2013

82 Yurkovetskiy L, "Gender bias in autoimmunity is influenced by microbiota" 39 : 400-412, 2013

83 Nuutila P, "Gender and insulin sensitivity in the heart and in skeletal muscles. Studies using positron emission tomography" 44 : 31-36, 1995

84 Kovats S, "Estrogen receptors regulate innate immune cells and signaling pathways" 294 : 63-69, 2015

85 Jacobson DL, "Epidemiology and estimated population burden of selected autoimmune diseases in the United States" 84 : 223-243, 1997

86 Daynes RA, "Emerging roles of PPARs in inflammation and immunity" 2 : 748-759, 2002

87 Jones LA, "Differential modulation of TLR3-and TLR4-mediated dendritic cell maturation and function by progesterone" 185 : 4525-4534, 2010

88 Phiel KL, "Differential estrogen receptor gene expression in human peripheral blood mononuclear cell populations" 97 : 107-113, 2005

89 Pisitkun P, "Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication" 312 : 1669-1672, 2006

90 Cipolletta D, "Appearance and disappearance of the mRNA signature characteristic of Treg cells in visceral adipose tissue: age, diet, and PPARγ effects" 112 : 482-487, 2015

91 Zhang MA, "Antagonizing peroxisome proliferator-activated receptor α activity selectively enhances Th1 immunity in male mice" 195 : 5189-5202, 2015

92 Lee BW, "Age-and sex-related changes in lymphocyte subpopulations of healthy Asian subjects : from birth to adulthood" 26 : 8-15, 1996

93 Chinetti G, "Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages" 273 : 25573-25580, 1998

94 Yang XY, "Activation of human T lymphocytes is inhibited by peroxisome proliferatoractivated receptor gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT" 275 : 4541-4544, 2000

95 Smith-Bouvier DL, "A role for sex chromosome complement in the female bias in autoimmune disease" 205 : 1099-1108, 2008

96 Kliewer SA, "A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation" 83 : 813-819, 1995

97 Forman BM, "15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma" 83 : 803-812, 1995