Mastitis is an inflammation of the
mammary gland tissue that can
lead to decreased milk production and altered milk composition, carrying
serious implications for the safety of dairy products. Although both
caffeic acid (CA) and umbilical cord-mesenchymal stem cells (UC-MSCs)
showed potential anti-inflammatory and immunomodulatory properties,
little is known about their combined roles in treating mastitis. Here,
we report the combined effects and mechanisms of CA and UC-MSCs on
lipopolysaccharide (LPS)-induced mastitis. Based on the network pharmacological
analysis, the potential relevant genes involved in the alleviating
effects of CA on LPS-induced mastitis were inferred. In LPS-treated
mammary epithelial cells, CA or/and UC-MSC conditioned medium (UC-MSC-CM)
inhibited the phosphorylation of p65, p50, p38, IκB, and MKK3/6
proteins and the expression of downstream inflammatory factors TNF-α,
IL-1β, IL-6, IL-8, and COX-2. Additionally, CA or/and hydrogel-loaded
UC-MSCs also suppressed the activation of the above inflammatory pathway,
leading to the alleviation of pathological damages in the LPS-induced
mouse mastitis model. UC-MSCs exhibited more significant effects than
CA, and the combined treatment of both was more effective. Our study
sheds light on the synergistic and complementary effects of CA and
UC-MSCs in alleviating mastitis, offering clues for understanding
the regulation of the p38-MAPK/NF-κB↔TNF-α signal
transduction loop in the tumor necrosis factor (TNF) pathway as a
potential mechanism. This study provides a theoretical basis for developing
a novel antibiotic alternative treatment of mastitis that may contribute
to reducing economic losses in animal husbandry and protecting public
health safety.