Male Macrophages and Fibroblasts from C57/BL6J Mice Are More Susceptible to Inflammatory Stimuli

Abstract

Mounting evidence argues for the significant impact of sex in numerous cardiac pathologies, including myocarditis. Macrophage polarization and activation of cardiac fibroblasts play a key role in myocardial inflammation and remodeling. However, the role of sex in these processes is still poorly understood. In this study, we investigated sex-specific alterations in the polarization of murine bone marrow-derived macrophages (BMMs) and the polarization-related changes in fibroblast activation. Cultured male and female murine BMMs from C57/BL6J mice were polarized into M1 (LPS) and M2 (IL-4/IL-13) macrophages. Furthermore, male and female cardiac fibroblasts from C57/BL6J mice were activated with TNF-α, TGF-β, or conditioned medium from M1 BMMs. We found a significant overexpression of M1 markers (c-fos, NFκB, TNF-α, and IL-1β) and M2 markers (MCP-1 and YM1) in male but not female activated macrophages. In addition, the ROS levels were higher in M1 male BMMs, indicating a stronger polarization. Similarly, the pro-fibrotic markers TGF-β and IL-1β were expressed in activated cardiac male fibroblasts at a significantly higher level than in female fibroblasts. In conclusion, the present study provides strong evidence for the male-specific polarization of BMMs and activation of cardiac fibroblasts in an inflammatory environment. The data show an increased inflammatory response and tissue remodeling in male mice.

RANK signaling in osteoclast precursors results in a more permissive epigenetic landscape and sexually divergent patterns of gene expression

“…By contrast, expression of TLR1, TLR2, and TLR9 was higher in male macrophages. These findings suggest that male naïve macrophages are more sensitive to TLR ligands and agree with prior findings of sexually dimorphic responses to inflammatory signals and induction of TLR expression in conjunction with pro-osteoclastogenic pathways ( Marriott, Bost & Huet-Hudson, 2006 ; Li et al, 2009 ; Barcena et al, 2021 ; Chen, Lainez & Coss, 2021 ; Song et al, 2022 ). The potency of some TLR ligands, such as bacterial lipopolysaccharide (LPS), to stimulate osteoclastogenesis of osteoclast precursors pre-committed with RANKL is well established ( Liu et al, 2009 ).…”

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

“…The analysis identified only 3 genes in non-infected BMDMs at 8 hours timepoint ( Figure 6E ): the lysophosphatidic acid receptor 1 ( Lpar1 ), the vascular endothelial growth receptor factor 2 ( Kdr ) and the cyclic AMP-responsive element-binding protein 3-like protein 2 ( Creb3l2 ). These genes play a role in inflammation ( 64 – 66 ), angiogenesis ( 67 ) and collagen synthesis ( 68 , 69 ), respectively, aspects that are hallmarks of Leishmania infection ( 70 , 71 ) and where in other experimental models sex differences have been described ( 72 – 74 ).…”

Macrophages and glial cells: Innate immune drivers of inflammatory arthritic pain perception from peripheral joints to the central nervous system

“…Estrogen receptor mediation of the pain phenotype evoked by IL-23 and IL-17 may be a hint for the different pathological outcomes observed in women and men regarding arthritis. In addition, despite data suggesting differential macrophage expansion between sexes in different pain models ( 112 ), and the well-described role of estrogen in macrophage polarization ( 269 , 270 ), the role of these sex differences in macrophage imbalance in arthritis remains unknown. Studies to fill this gap are warranted and will be beneficial in leading to effective therapies for arthritis pain for all patients.…”