The Role of Progestogens in Regulating Matrix Metalloproteinase Activity in Macrophages and Microglial Cells

Abstract

Although the systemic effects of progestogens have been extensively studied, little is known in regards to the cellular effects of these compounds. Using a cellular model for vascular (macrophages) and brain (microglial) cells, we studied the effects of various progestogens, either alone or in combination with 17β-estradiol (E(2)) on the activity of matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme involved in vascular remodeling and plaque destabilization in cardiovascular events, blood-brain barrier breakdown in stroke and brain regeneration and neurovascular remodeling during repair phases of brain injury. In the absence of E(2), medroxyprogesterone acetate (MPA), a synthetic progestogen and progesterone (PG) metabolites tended to increase MMP-9 enzyme activity in macrophages and microglial cells, whereas PG decreased such activity in macrophages; exceptions being that MPA and the PG metabolite, pregnanediol (Pdiol) had no effect on macrophage MMP-9 enzyme activity and PG had no effect on microglial cell MMP-9 enzyme activity. In the presence of E(2), an opposite affect was observed whereby MPA and the PG metabolites tended to decrease MMP-9 enzyme activity from macrophages and microglial cells, whereas PG had no effect; exceptions being that MPA and Pdiol had no effect on macrophage MMP-9 enzyme activity. In conclusion, these results demonstrate that the effects of PG, PG metabolites and MPA on MMP-9 enzyme activity differ across vascular and brain cells when administered alone or in combination with E(2) which could have important mechanistic implications for hormone therapy.

Progesterone Improves Neurobehavioral Outcome in Models of Intracerebral Hemorrhage

“…Further, progesterone decreases reactive oxygen species through its effects on mitochondria in multiple tissue types, including the brain [43,44]. Progesterone also modulates microglial cytokine expression [9,10,11,12]. In the present study, progesterone decreased brain edema, microglial proliferation/macrophage recruitment, and cytokine expression, while hematoma volume was constant.…”

“…Indeed, when exogenous progesterone was administered following ICH, male rats showed decreased brain edema and improved neurobehavioral outcome [8]. Progesterone plays many roles in the central nervous system and is known to modulate neuroinflammation through effects on microglia [9,10,11,12], which are thought to be important in the post-ICH inflammatory response [13]. …”

Medroxyprogesterone Acetate Impairs Amyloid Beta Degradation in a Matrix Metalloproteinase-9 Dependent Manner

“…The present study investigated the expression of MMP-9 in C6 glial cells treated with MPA. Several reports have demonstrated that MPA can alter MMP-9 levels, where levels are increased in macrophages and, alternatively, reduced in BV2 microglial, endometrial cancer, and primary amnion epithelial cells (Di Nezza et al, 2003;Hwang-Levine et al, 2011;Allen et al, 2019). Consistent with these reports, we found that MMP-9 protein expression and enzymatic activity is lowered by treatment with MPA.…”

“…MMP-9 is critical for cellular processes involved in learning and memory, as it regulates dendritic spine morphology, maintains late-phase long term potentiation (LTP), and controls postnatal brain development (Nagy et al, 2006;Michaluk et al, 2011;Kamat et al, 2014;Gorkiewicz et al, 2015;Reinhard et al, 2015;Kaczmarek, 2016). MPA has also been shown to alter MMP-9 activity and production in BV2 microglial, cancer, and epithelial cells (Di Nezza et al, 2003;Hwang-Levine et al, 2011;Allen et al, 2019). Additionally, the secretion of MMP-9 was found to be negatively impacted by MPA in the aforementioned cell types (Deb and Gottschall, 1996;Deb et al, 2003;Hwang-Levine et al, 2011;Allen et al, 2019).…”

“…MPA has also been shown to alter MMP-9 activity and production in BV2 microglial, cancer, and epithelial cells (Di Nezza et al, 2003;Hwang-Levine et al, 2011;Allen et al, 2019). Additionally, the secretion of MMP-9 was found to be negatively impacted by MPA in the aforementioned cell types (Deb and Gottschall, 1996;Deb et al, 2003;Hwang-Levine et al, 2011;Allen et al, 2019). It is currently unknown if hormonal modulation of glial-secreted MMP-9, using MPA, impacts degradation of Aβ.…”