The Role of Peroxisome Proliferator-activated Receptor Alpha in the Regulation of Sex Differences in T Helper 1 Immunity

It is reported that female CD4+ T cells are biased towards T helper (Th) 1 cytokine production, whereas male CD4+ T cells are biased towards Th2. It has been suggested that the female bias in Th1 immunity is the reason why females not only generate enhanced anti-viral and anti-tumour responses, but also are more likely to develop certain autoimmune diseases than males. Our group previously reported that the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) has a sex-specific role in negatively regulating Th1 immunity in mice. The objective of the thesis is to further explore the roles of PPARα in the regulation of sex differences in Th immunity. We first investigated sex differences in Th cytokine production in SJL mice and human primary CD4+ T cells. We observed that female CD4+ T cells of both species produced higher levels of interferon (IFN)-γ and lower levels of IL-17 than male counterparts. Furthermore, we showed that this sex bias in Th immunity was controlled by androgens. The effects of androgens in suppressing Th1 immunity were shown to be mediated through PPARα. Moreover, we showed that PPARα activity negatively correlated with IFN-γ production by CD4+ T cells. Subsequent studies in mice identified IFN-γ as the gene repressed by PPARα. We showed that this repression was mediated through the recruitment of PPARα and the nuclear receptor co-repressor 1(NCOR)-containing co-repressor complex to certain conserved non-coding sequences (CNS) at the Ifng locus in male T cells. Conversely, repressing PPARα activity with the antagonist NXT-1120 lead to global derepression at the Ifng locus and increased IFN-γ production. This control of IFN-γ production by PPARα in male T cells also extended to natural killer (NK) T cells and CD8+ T cells. On the other hand, we found that the sex difference in Th17 immunity was regulated by PPARγ. Androgens decreased PPARγ mRNAs in murine and human CD4+ T cells. Furthermore, knocking down PPARγ expression using siRNAs was associated with higher IL-17 production by female CD4+ T cells. Taken together, these findings have furthered the understanding of sex differences in Th immunity.Ph.D

An Australia–China strategy for cooperation on recovery and reconstruction after COVID-19

A key feature of the Australia-China bilateral economic relationship during the global pandemic has been the growth in importance of trade between the two countries. China has recently accounted for as much as 46 per cent of all Australia’s merchandise exports, primarily driven by iron ore and other strategic raw materials as the Chinese market has held firm. That is reflected in strong commodity prices and has cushioned the economic downturn in Australia during the COVID lockdown. Australia’s energy and iron ore exports will help fuel a strong economic recovery in China with low-cost, high-quality inputs into its global supply chains. The relationship is important for the economic recovery of both countries and the Asian region. The deepening economic interdependence is enormously beneficial to both countries but stands in marked contrast to the deterioration of the bilateral political relationship that has coincided with increased uncertainty in the international political environment. Foreign investment and trade in services — education, tourism and other services — will not automatically revert to pre-pandemic levels without work to repair the fracture in the relationship. The challenge is to rebuild trust between Australia and China, and in the management of the bilateral relationship. That should be guided by the many shared interests that both countries have in regional and global affairs. A circuit breaker is sensibly the joint pursuit of regional and global efforts to address the health and economic effects of the COVID-19 pandemic. That is the biggest challenge that both countries face in the world today. The priority areas for cooperation are outlined in this paper. The paper details opportunities for bilateral cooperation between Australia and China with their partners in the region suggested by ABER’s An Asian Strategy for recovery and reconstruction after COVID-19 (http://eaber.org/covid19). In the aftermath of COVID-19, Australia and China share strong interests in ensuring public health and safety, financial stability and open and rules-based trade in the region. Both governments can contribute towards these goals effectively by working actively together in multilateral settings such as the ASEAN+6 grouping, EAS, APEC and the G20.This report was commisioned by Australian Government and CCIEE

Sex-specific T-cell regulation of angiotensin II-dependent hypertension

Studies suggest T cells modulate arterial pressure. Because robust sex differences exist in the immune system and in hypertension, we investigated sex differences in T-cell modulation of angiotensin II-induced increases in mean arterial pressure in male (M) and female (F) wild-type and recombination-activating-gene-1-deficient (Rag1(-/-)) mice. Sex differences in peak mean arterial pressure in wild-type were lost in Rag1(-/-) mice (mm Hg: wild-type-F, 136±4.9 versus wild-type-M, 153±1.7; P\u3c0.02; Rag1(-/-)-F, 135±2.1 versus Rag1(-/-)-M, 141±3.8). Peak mean arterial pressure was 13 mm Hg higher after adoptive transfer of male (CD3(M)→Rag1(-/-)-M) versus female (CD3(F)→Rag1(-/-)-M) T cells. CD3(M)→Rag1(-/-)-M mice exhibited higher splenic frequencies of proinflammatory interleukin-17A (2.4-fold) and tumor necrosis factor-α (2.2-fold)-producing T cells and lower plasma levels (13-fold) and renal mRNA expression (2.4-fold) of interleukin-10, whereas CD3(F)→Rag1(-/-)-M mice displayed a higher activation state in general and T-helper-1-biased renal inflammation. Greater T-cell infiltration into perivascular adipose tissue and kidney associated with increased pressor responses to angiotensin II if the T cell donor was male but not female and these sex differences in T-cell subset expansion and tissue infiltration were maintained for 7 to 8 weeks within the male host. Thus, the adaptive immune response and role of pro- and anti-inflammatory cytokine signaling in hypertension are distinct between the sexes and need to be understood to improve therapeutics for hypertension-associated disease in both men and women

The gut-joint axis mediates the TNF-induced RA process and PBMT therapeutic effects through the metabolites of gut microbiota

ABSTRACTThe gut-joint axis, one of the mechanisms that mediates the onset and progression of joint and related diseases through gut microbiota, and shows the potential as therapeutic target. A variety of drugs exert therapeutic effects on rheumatoid arthritis (RA) through the gut-joint axis. However, the anti-inflammatory and immunomodulatory effect of novel photobiomodulatory therapy (PBMT) on RA need further validation and the involvement of gut-joint axis in this process remains unknown. The present study demonstrated the beneficial effects of PBMT on RA, where we found the restoration of gut microbiota homeostasis, and the related key pathways and metabolites after PBMT. We also discovered that the therapeutic effects of PBMT on RA mainly through the gut-joint axis, in which the amino acid metabolites (Alanine and N-acetyl aspartate) play the key role and rely on the activity of metabolic enzymes in the target organs. Together, the results prove that the metabolites of amino acid from gut microbiota mediate the regulation effect on the gut-joint axis and the therapeutic effect on rheumatoid arthritis of PBMT