Life sciences · 2026
Chromatin regulator PTIP: A critical safeguard against B cell apoptosis and exhaustion in TLR-4-driven inflammation.
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Su Dan, Xu Yaqin
Аннотация
AIMS: B cells play dual roles in host defense and immunosuppression during inflammatory diseases such as sepsis. We investigated the role of the chromatin regulator PTIP in maintaining B cell survival and functional integrity during innate immune activation.
MATERIALS AND METHODS: B cell-specific PTIP-deficient mice were subjected to lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4)-mediated inflammation. Apoptosis, exhaustion phenotypes, cytokine production, and survival were assessed. Molecular mechanisms were dissected through analysis of apoptotic regulators and inflammatory cytokine signaling pathways.
KEY FINDINGS: PTIP deficiency significantly increased activation-induced cell death by upregulating Fas and downregulating Bcl-2, thereby enhancing both extrinsic and intrinsic apoptotic pathways. Mechanistically, PTIP suppressed Fas expression via its N-terminal BRCT1-2 domains independently of BAFF-R, TACI, or IRF4 signaling. Instead, excessive TNF-α and IFN-γ signaling promoted Fas upregulation in PTIP-deficient B cells, linking inflammatory cytokine signals to chromatin-dependent apoptotic regulation. In addition to promoting apoptosis, loss of PTIP accelerated B cell exhaustion during acute inflammation, characterized by increased IL-10 production, elevated inhibitory receptor expression, and reduced MHC II expression. These cellular defects translated in vivo into heightened systemic immunosuppression, aggravated clinical manifestations, and reduced survival following LPS challenge.
SIGNIFICANCE: Our findings identify PTIP as a critical chromatin-based regulator of B cell homeostasis during innate immune responses. Targeting PTIP-dependent pathways may provide therapeutic opportunities to restore immune balance in inflammatory diseases.
MATERIALS AND METHODS: B cell-specific PTIP-deficient mice were subjected to lipopolysaccharide (LPS)-induced Toll-like receptor 4 (TLR4)-mediated inflammation. Apoptosis, exhaustion phenotypes, cytokine production, and survival were assessed. Molecular mechanisms were dissected through analysis of apoptotic regulators and inflammatory cytokine signaling pathways.
KEY FINDINGS: PTIP deficiency significantly increased activation-induced cell death by upregulating Fas and downregulating Bcl-2, thereby enhancing both extrinsic and intrinsic apoptotic pathways. Mechanistically, PTIP suppressed Fas expression via its N-terminal BRCT1-2 domains independently of BAFF-R, TACI, or IRF4 signaling. Instead, excessive TNF-α and IFN-γ signaling promoted Fas upregulation in PTIP-deficient B cells, linking inflammatory cytokine signals to chromatin-dependent apoptotic regulation. In addition to promoting apoptosis, loss of PTIP accelerated B cell exhaustion during acute inflammation, characterized by increased IL-10 production, elevated inhibitory receptor expression, and reduced MHC II expression. These cellular defects translated in vivo into heightened systemic immunosuppression, aggravated clinical manifestations, and reduced survival following LPS challenge.
SIGNIFICANCE: Our findings identify PTIP as a critical chromatin-based regulator of B cell homeostasis during innate immune responses. Targeting PTIP-dependent pathways may provide therapeutic opportunities to restore immune balance in inflammatory diseases.