TLR2/TLR4-Enhanced TIPE2 Expression Is Involved in Post-Hemorrhagic Shock Mesenteric Lymph-Induced Activation of CD4+T Cells

Purpose: Post hemorrhagic shock mesenteric lymph (PHSML) return contributes to CD4(+) T cell dysfunction, which leads to immune dysfunction and uncontrolled inflammatory response. Tumor necrosis factor alpha induced protein 8 like-2 (TIPE2) is one of the essential proteins to maintain the immune homeostasis. This study investigated the role of TIPE2 in regulation of CD4(+) T lymphocyte function in interaction of PHSML and TLR2/TLR4.& nbsp;Methods: The splenic CD4(+) T cells were isolated from various mice (WT, TLR2(-/-), TLR4(-/-)) by immunomagnetic beads, and stimulated with PHSML, normal lymphatic fluid (NML), respectively. Application of TIPE2-carrying interfering fragments of lentivirus were transfected to WT, TLR4(-/-), and TLR2(-/-) CD4(+) T cells, respectively. After interference of TIPE2, they were stimulated with PHSML and NML for the examinations of TIPE2, TLR2, and TLR4 mRNA expressions, proliferation, activation molecules on surface, and cytokine secretion function.& nbsp;Results: PHSML stimulation significantly upregulated TIPE2, TLR2, and TLR4 mRNA expressions, decreased proliferation, CD25 expression, and IFN-gamma secretion, and increased the secretion ability of IL-4 in WT CD4(+) T cells. TIPE2 silencing enhanced proliferative capacity, upregulated CD25 expression, and increased IFN gamma secretion in CD4(+) T cells. PHSML stimulated TLR2(-/-)CD4(+) T or TLR4(-/-)CD4(+) T cells of which TIPE2 were silenced. TLR2 or TLR4 knockout attenuated PHSML-induced CD4(+) T cells dysfunction; PHSML stimulation of silent TIPE2-expressing TLR2(-/-)CD4(+) T or TLR4(-/-)CD4(+) T revealed that the coexistence of low TIPE2 expression with lack of TLR2 or TLR4 eliminated this beneficial effect.& nbsp;Conclusion: TIPE2 improves the PHSML-mediated CD4(+)T cells dysfunction by regulating TLR2/TLR4 pathway, providing a new intervention target following hemorrhagic shock-induced immune dysfunction.