The complement receptor 3 (CD11b/CD18) agonist Leukadherin-1 suppresses human innate inflammatory signalling

Area of Science:

• Immunology
• Molecular Biology
• Autoimmune Diseases

Background:

• Complement receptor 3 (CR3) is crucial for myeloid and NK cell function.
• The ITGAM rs1143679 polymorphism (R77H variant) is linked to systemic lupus erythematosus (SLE) and impaired CR3 function.
• CR3's role in NK cells remains largely unknown.

Purpose of the Study:

• To investigate the effect of Leukadherin-1, a CR3 agonist, on NK cell and monocyte inflammatory responses.
• To determine if the SLE-associated CR3 R77H variant influences Leukadherin-1's effects.
• To explore the therapeutic potential of CR3 activation in autoimmune diseases.

Main Methods:

• Utilized Leukadherin-1 to stimulate CR3 on NK cells and monocytes.
• Measured cytokine secretion (IFN-γ, TNF, MIP-1β, IL-10, IL-1β, IL-6) following various stimuli (monokines, IL-12/IL-15, IL-12/IL-18, TLR-2, TLR-7/8).
• Assessed STAT5 phosphorylation and CR3 expression in cells from R77H variant homozygous donors.

Main Results:

• Leukadherin-1 pretreatment reduced pro-inflammatory cytokine secretion from NK cells and monocytes.
• CR3 activation modulated STAT5 phosphorylation and IL-10 secretion in NK cells.
• The R77H variant did not impact NK cell responses to Leukadherin-1 or CR3 expression.

Conclusions:

• CR3 activation by Leukadherin-1 potently modifies innate immune inflammatory signaling, including in NK cells.
• Leukadherin-1's anti-inflammatory effects are independent of the SLE-risk CR3 genotype.
• Leukadherin-1 shows promise as a therapeutic agent for autoimmune diseases like SLE.