The skin is the most common site of Staphylococcus aureus infection,which can lead to various diseases,including invasive and life-threatening infections,through evasion of host defense.However,little is known about t...The skin is the most common site of Staphylococcus aureus infection,which can lead to various diseases,including invasive and life-threatening infections,through evasion of host defense.However,little is known about the host factors that facilitate the innate immune evasion of S.aureus in the skin.Chemerin,which is abundantly expressed in the skin and can be activated by proteases derived from S.aureus,has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1.Here,we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S.aureus in a mouse model of cutaneous infection,whereas chemerin overexpression,which mimics high levels of chemerin in obese individuals,exacerbates S.aureus cutaneous infection.Mechanistically,we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S.aureus-induced IL-33 expression,leading to impaired skin neutrophilia and bacterial clearance.CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S.aureus by inhibiting Akt activation in mouse keratinocytes.Thus,our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S.aureus in vivo and likely increases susceptibility to S.aureus infection in obese individuals.展开更多
基金Shanghai Science and Technology Commission 23ZR1461500(to RH)Key Laboratory of Medical Molecular Virology(MOE/NHC)FDMVK-2021001(to RH)+1 种基金The National Natural Science Foundation of China Grant 82271138(to HL)National Key Research and Development Program of China 2020YFC2005003(to JC).
文摘The skin is the most common site of Staphylococcus aureus infection,which can lead to various diseases,including invasive and life-threatening infections,through evasion of host defense.However,little is known about the host factors that facilitate the innate immune evasion of S.aureus in the skin.Chemerin,which is abundantly expressed in the skin and can be activated by proteases derived from S.aureus,has both direct bacteria-killing activity and immunomodulatory effects via interactions with its receptor CMKLR1.Here,we demonstrate that a lack of the chemerin/CMKLR1 axis increases the neutrophil-mediated host defense against S.aureus in a mouse model of cutaneous infection,whereas chemerin overexpression,which mimics high levels of chemerin in obese individuals,exacerbates S.aureus cutaneous infection.Mechanistically,we identified keratinocytes that express CMKLR1 as the main target of chemerin to suppress S.aureus-induced IL-33 expression,leading to impaired skin neutrophilia and bacterial clearance.CMKLR1 signaling specifically inhibits IL-33 expression induced by cell wall components but not secreted proteins of S.aureus by inhibiting Akt activation in mouse keratinocytes.Thus,our study revealed that the immunomodulatory effect of the chemerin/CMKLR1 axis mediates innate immune evasion of S.aureus in vivo and likely increases susceptibility to S.aureus infection in obese individuals.
