Complement Component C1q Programs a Pro-Efferocytic Phenotype while Limiting TNFα Production in Primary Mouse and...

Area of Science:

• Immunology
• Molecular Biology
• Autoimmunity

Background:

• Complement component C1q deficiency is linked to impaired efferocytosis and inflammation in lupus.
• Understanding C1q's regulatory roles in macrophages is crucial for autoimmune and inflammatory diseases.

Purpose of the Study:

• To investigate C1q's regulation of TNFα/IL-6 expression and efferocytosis in mouse and human macrophages.
• To elucidate the molecular mechanisms underlying C1q's effects on macrophage functions.

Main Methods:

• Primary mouse bone marrow-derived macrophages and human monocyte-derived macrophages were used.
• Investigated C1q's effects on lipopolysaccharide (LPS)-dependent TNFα and IL-6 production.
• Assessed C1q's impact on efferocytosis and related molecular pathways (Mer, Gas6, Axl).

Main Results:

• C1q downregulated LPS-induced TNFα production in both mouse and human macrophages, with differential kinetics.
• IL-6 production was unaffected in mouse macrophages but upregulated in human macrophages by C1q.
• C1q-dependent efferocytosis programming in human macrophages required protein synthesis but not Mer or Axl upregulation, unlike in mouse macrophages.
• C1q collagen-like tails alone promoted phagocytosis of antibody-coated targets but did not enhance efferocytosis or dampen TNFα.

Conclusions:

• C1q plays a complex role in regulating macrophage inflammatory responses and efferocytosis.
• Species-specific mechanisms mediate C1q's effects on efferocytosis and cytokine production.
• These findings deepen the understanding of C1q's contribution to autoimmunity and chronic inflammation.