Sex-Biased Control of Inflammation and Metabolism by a Mitochondrial Nod-Like Receptor

Abstract

Mitochondria regulate steroid hormone synthesis, and in turn sex hormones regulate mitochondrial function for maintaining cellular homeostasis and controlling inflammation. This crosstalk can explain sex differences observed in several pathologies such as in metabolic or inflammatory disorders. Nod-like receptor X1 (NLRX1) is a mitochondria-associated innate receptor that could modulate metabolic functions and attenuates inflammatory responses. Here, we showed that in an infectious model with the human protozoan parasite, Leishmania guyanensis, NLRX1 attenuated inflammation in females but not in male mice. Analysis of infected female and male bone marrow derived macrophages showed both sex- and genotype-specific differences in both inflammatory and metabolic profiles with increased type I interferon production, mitochondrial respiration, and glycolytic rate in Nlrx1-deficient female BMDMs in comparison to wild-type cells, while no differences were observed between males. Transcriptomics of female and male BMDMs revealed an altered steroid hormone signaling in Nlrx1-deficient cells, and a “masculinization” of Nlrx1-deficient female BMDMs. Thus, our findings suggest that NLRX1 prevents uncontrolled inflammation and metabolism in females and therefore may contribute to the sex differences observed in infectious and inflammatory diseases.

Targeting cell death pathways in intestinal ischemia-reperfusion injury: a comprehensive review

“…In vivo, locked nucleic acid-modified inhibition reduces I/R-induced systemic inflammation and apoptosis by restoring the autophagy flux [ 97 ]. In the mitochondria, NLRX1 is highly expressed in the gut and can regulate ROS production, mitochondrial damage, autophagy, and apoptosis [ 103 , 104 ]. Some studies examined the role of NLRX1 in mitochondrial homeostasis and apoptosis after intestinal I/R injury and found that NLRX1 was significantly downregulated after intestinal I/R injury [ 98 ].…”

Sex Differences in Sphingosine-1-Phosphate Levels Are Dependent on Ceramide Synthase 1 and Ceramidase in Lung Physiology and Tumor Conditions

“…In particular, the activation of TLR9 in lung epithelial cells can promote the synthesis of S1P, thereby increasing the levels of TNF-α [ 19 ] as well as cell proliferation [ 3 ] in both a TLR9- and S1PR3-dependent manner. As it was recently proved that the activation of the immune system and thus the ensuing inflammatory pathways are strictly related to sex, in that males and females differ in their immunological responses to foreign and self-antigens, suggesting that hormones can affect the immune response [ 20 , 21 , 22 , 23 ], it is likely that sex is a biological variable that can impact both lung physiology and pathologies. In accordance with this, it was shown that estrogens can stimulate S1P synthesis in females [ 24 ].…”