Myometrial-derived CXCL12 promotes lipopolysaccharide induced preterm labour by regulating macrophage migration, polarization and function in mice.
Lijuan ZhangRamanaiah MamillapalliShutaro HabataMolly McAdowHugh S TaylorPublished in: Journal of cellular and molecular medicine (2022)
Preterm birth is a major contributor to neonatal mortality and morbidity. Infection results in elevation of inflammation-related cytokines followed by infiltration of immune cells into gestational tissue. CXCL12 levels are elevated in preterm birth indicating it may have a role in preterm labour (PTL); however, the pathophysiological correlations between CXCL12/CXCR4 signalling and premature labour are poorly understood. In this study, PTL was induced using lipopolysaccharide (LPS) in a murine model. LPS induced CXCL12 RNA and protein levels significantly and specifically in myometrium compared with controls (3-fold and 3.5-fold respectively). Highest levels were found just before the start of labour. LPS also enhanced the infiltration of neutrophils, macrophages and T cells, and induced macrophage M1 polarization. In vitro studies showed that condition medium from LPS-treated primary smooth muscle cells (SMC) induced macrophage migration, M1 polarization and upregulated inflammation-related cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor alpha (TNF-α). AMD3100 treatment in pregnant mice led to a significant decrease in the rate of PTL (70%), prolonged pregnancy duration and suppressed macrophage infiltration into gestation tissue by 2.5-fold. Further, in-vitro treatment of SMC by AMD3100 suppressed the macrophage migration, decreased polarization and downregulated IL-1, IL-6 and TNF-α expression. LPS treatment in pregnant mice induced PTL by increasing myometrial CXCL12, which recruits immune cells that in turn produce inflammation-related cytokines. These effects stimulated by LPS were completely reversed by AMD3100 through blocking of CXCL12/CXCR4 signalling. Thus, the CXCL12/CXCR4 axis presents an excellent target for preventing infection and inflammation-related PTL.
Keyphrases
- preterm birth
- inflammatory response
- lipopolysaccharide induced
- lps induced
- gestational age
- low birth weight
- oxidative stress
- diabetic rats
- high glucose
- adipose tissue
- rheumatoid arthritis
- pregnant women
- drug induced
- anti inflammatory
- preterm infants
- high fat diet induced
- birth weight
- coronary artery disease
- weight gain
- combination therapy
- immune response
- poor prognosis
- long non coding rna
- endothelial cells
- cardiovascular disease
- type diabetes
- skeletal muscle
- insulin resistance
- physical activity
- cardiovascular events
- risk factors
- pregnancy outcomes