Regulatory Mechanism Of Macrophage Polarization In Staphylococcus Aureus Infection

Macrophages are the body's very first line of defense against invasions by foreign bacteria.The functions of macrophages that lead to effective host responses are critical for protection against Staphylococcus aureus(S.aureus).Although macrophages are versatile cells that play a variety of roles,their functions in S.aureus deep tissue infection,especially the liver,have not been fully defined.Here,we revealed a macrophage accumulation pattern in the liver after S.aureus infection and an essential role for T cell responses:macrophages formed sporadic aggregates in the liver during infection.Within those aggregates,macrophages co-localized with T cells and were indispensable for their infiltration.S.aureus initially countered by macrophages trigger macrophage accumulation and induce inflammatory responses through surface receptors,especially toll-like receptor 2(TLR2).However,the regulatory mechanism of macrophage polarization upon TLR2 activation have not yet been clarified.Here,we have focused on the mechanisms underlying the polarization of macrophages in Forkhead box transcription factor 01(FoxO1)conditional knockout LysCre/+FoxO1fl/fl mice following S.aureus infection report herein that macrophage M1-M2 polarization via TLR2 is intrinsically regulated by FoxO1.Indeed,for effective FoxO1 activity,stimulation of TLR2 is essential.However,following S.aureus infection,FoxO1 can be down-regulated in macrophage by TLR2-mediated activation of PI3K/Akt and c-Raf/MEK/ERK pathway at the same time to restrain active FoxO1 function in promoting inflammatory response.Phosphorylation of FoxO1 through TLR2 is a newly discovered balancing mechanism in macrophage M1-M2 polarization during S.aureus infection.Following infection in LysCre/+FoxO1fl/fl mice,mice became more susceptible to S.aureus.LysCre/+FoxOlfl/fl mice reduce not only macrophage aggregates formation in the liver,but also T cell infiltrations.Reduced macrophage aggregation in the liver and attenuated Th1 and Th17 responses both exacerbated S.aureus infection.FoxO1 abrogation reduced M1 pro-inflammatory responses triggered by S.aureus and enhanced M2 polarization in macrophages.Production of proinflammatory mediators and functional surface markers were all decreased in FoxO1 knockout macrophages.In contrast,overexpression of FoxO1 in macrophages showed reversed phenomenon.In conclusion,our research in dynamic regulation of TLR2 signaling and macrophage functions in the liver can help towards a comprehensive understanding of macrophage polarization in response to invasive S.aureus infection.