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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Absence of PD-L1 signaling hinders macrophage defense against Mycobacterium tuberculosis via upregulating STAT3/IL-6
Peijie Qu1, Xinyu Li2, Weihuang Liu3
1Department of Anatomy, Hubei Province Key Laboratory of Allergy and Immunology, Wuhan University TaiKang Medical School (School of Basic Medical Sciences), Wuhan 430071, China; Institute of Laboratory Animal Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.
Abstract:
The blockade of programmed death-ligand 1 (PD-L1) pathway has been clinically used in cancer immunotherapy, while its effects on infectious diseases remain elusive. Roles of PD-L1 signaling in the macrophage-mediated innate immune defense against M.tb is unclear. In this study, the outcomes of tuberculosis (TB) in wild-type (WT) mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1ΔΜΦ) mice were compared. Treatment with anti-PD-L1 or anti-PD-1 benefited protection against M.tb infection in WT mice, while Pdl1ΔΜΦ mice exhibited the increased susceptibility to M.tb infection. Mechanistically, the absence of PD-L1 signaling impaired M.tb killing by macrophages. Furthermore, elevated STAT3 activation was found in PD-L1-deficient macrophages, leading to increased interleukin (IL)-6 production and reduced inducible nitric oxide synthase (iNOS) expression. Inhibiting STAT3 phosphorylation partially impeded the increase in IL-6 production and restored iNOS expression in these PD-L1-deficient cells. These findings provide valuable insights into the complexity and mechanisms underlying anti-PD-L1 therapy in the context of tuberculosis.
Insights
Programmed death-ligand 1 (PD-L1) blockade aids tuberculosis defense in wild-type mice but harms it in macrophage-specific knockout mice. PD-L1 deficiency impairs macrophage function via STAT3 signaling.
Area of Science:
- Immunology
- Infectious Diseases
- Cancer Immunotherapy
Background:
- Programmed death-ligand 1 (PD-L1) pathway blockade is a cancer immunotherapy strategy.
- The role of PD-L1 in innate immune defense against Mycobacterium tuberculosis (M.tb) is not well understood.
Purpose of the Study:
- To investigate the role of PD-L1 signaling in macrophage-mediated immunity against M.tb.
- To compare the effects of anti-PD-1/PD-L1 therapy in wild-type mice versus PD-L1 deficient mice.
Main Methods:
- Comparison of tuberculosis outcomes in wild-type mice treated with anti-PD-1/PD-L1 therapy and macrophage-specific Pdl1-knockout (Pdl1ΔMΦ) mice.
- Mechanistic studies involving macrophage function, STAT3 activation, and cytokine production (IL-6, iNOS).
Main Results:
- Anti-PD-L1 or anti-PD-1 therapy improved protection against M.tb in wild-type mice.
- Pdl1ΔMΦ mice showed increased susceptibility to M.tb infection.
- PD-L1 deficiency impaired macrophage M.tb killing, increased STAT3 activation, elevated IL-6, and reduced iNOS expression.
- STAT3 inhibition partially reversed IL-6 increase and restored iNOS expression in PD-L1 deficient macrophages.
Conclusions:
- PD-L1 signaling is crucial for macrophage-mediated innate immune defense against M.tb.
- Dysregulation of STAT3, IL-6, and iNOS pathways contributes to increased susceptibility in PD-L1 deficient macrophages.
- Findings offer insights into PD-L1 blockade therapy in tuberculosis contexts.
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