CD11b suppresses TLR activation of nonclassical monocytes to reduce primary graft dysfunction after lung...

Area of Science:

• Immunology
• Transplantation Biology
• Pulmonary Medicine

Background:

• Primary graft dysfunction (PGD) is a major cause of mortality and chronic lung allograft dysfunction after lung transplantation.
• The underlying mechanisms driving PGD variability remain largely unknown.
• Nonclassical monocytes play a role in PGD pathogenesis.

Purpose of the Study:

• To elucidate the mechanistic basis of PGD following lung transplantation.
• To identify novel therapeutic targets for preventing PGD.

Main Methods:

• Utilized a murine orthotopic vascularized lung transplant model.
• Investigated the role of Toll-like receptors (TLR2 and TLR4) and MyD88 signaling in nonclassical monocytes.
• Examined the function of CD11b and HMGB1 in PGD development.
• Assessed the therapeutic potential of a CD11b agonist (leukadherin-1) and an HMGB1 inhibitor.

Main Results:

• Redundant activation of TLR2/4 on nonclassical monocytes leads to MyD88 activation and CXCL2 release, attracting neutrophils and exacerbating PGD.
• Deletion of CD11b in nonclassical monocytes increased CXCL2 production and worsened PGD.
• Administration of a CD11b agonist to the donor lung abrogated CXCL2 production and PGD.
• Increased HMGB1 levels post-reperfusion induced CXCL2 production via TLR4/MyD88.
• HMGB1 inhibition attenuated PGD.

Conclusions:

• CD11b functions as a crucial molecular brake preventing excessive neutrophil recruitment by nonclassical monocytes.
• Targeting CD11b or HMGB1 in the donor lung presents a promising therapeutic strategy to prevent PGD in lung transplant recipients.