The role of ten-eleven translocation 2 （Tet2） in host defense against methicillin-resistant Staphylococcus aureus （MRSA） infection and its potential effects on the inflammatory response and autophagy in mouse skin were studied.Subcutaneous inoculation of MRSA was performed in C57BL/6J Wild-type （Tet2^+/+） and Tet2 knockout （Tet2^-/-） mice to establish a murine skin abscess model.The changes in lesions of mouse skin were monitored，the tissue bacterial loads were measured.The expression of inflammatory factors and autophagy related genes were detected.The result showed that Tet2^-/- mice infected with MRSA had more severe damage in skin and higher tissue bacterial loads （P<0.01） compared with Tet2^+/+ mice.Changes in severe histopathology including the thickened epidermis，the dermis with broken collagen fibers，sebaceous gland atrophy and numerous infiltrated extensive inflammatory cells were observed in MRSA-infected Tet2^-/- mice.A large number of autophagosomal architectures were formed in MRSA-infected Tet2^+/+ mice under examination with transmission electron microscopy，whereas they are rarely found in Tet2^-/- mice.The result of Real-time quantitative PCR detection showed that Tet2 deficiency resulted in extremely significant up-regulation of pro-inflammatory mediators including IL-1 and TNF-α （P<0.01），alongside down-regulation of anti-inflammatory cytokines IL-10 （P<0.05） and TGF-β （P<0.001）.Sqstm1 （p62） and Map1lc3b （LC3b） as two classical indicators for autophagy in Tet2^-/- mice were elevated and decreased compared to that in Tet2^+/+ mice （P<0.01） during MRSA-infection.The result of immunohistochemistry staining showed that there was extensive expression of p62 and decreased expression of LC3b in Tet2-deficient mice，indicating that Tet2 plays a protective role in MRSA-mediated skin injury by promoting autophagy，and its absence results in impaired autophagy and dysregulated inflammatory responses，ultimately leading to the exacerbated pathology of skin tissue in infected mice.