Huang, Shaina Chor Mei; (2025) ArpC5 containing Arp2/3 iso-complexes are essential for immune homeostasis. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Arp2/3 is a seven-subunit complex that is responsible for generating branched actin networks, which are essential for many biological processes. In mammals, three of the seven subunits exist as two isoforms: Arp3/3B, ArpC1A/1B, and ArpC5/5L. ArpC1B deficiency has been reported to lead to a broad spectrum of immunological dysfunctions in humans that resemble Wiskott-Aldrich syndrome. More recently, novel pathogenic ARPC5 variants were discovered in patients with multiple developmental abnormalities and immune system disorders, leading to early mortality. To elucidate the role of ArpC5 in immune homeostasis, I generated hematopoietic-specific ArpC5-knockout mice (ArpC5∆Vav1Cre). These mice developed pale bone marrow, splenomegaly, and spontaneous enteritis. Notably, these phenotypes were absent in mice lacking the alternative isoform, ArpC5L. Further analysis revealed that the microbiota is essential in driving inflammation in ArpC5∆Vav1Cre mice, suggesting a breach in the mucosal barrier. Moreover, reintroducing wild type innate immune cells rescued ArpC5∆Vav1Cre mice from developing inflammatory phenotypes, highlighting the essential role of ArpC5 in maintaining host-microbiota homeostasis. Flow cytometry and live cell imaging demonstrated that ArpC5-deficient macrophages were defective in phagocytosis and efferocytosis. This dysfunction likely underlies the compromised mucosal barrier, leading to systemic infection and unresolved inflammation in ArpC5∆Vav1Cre mice.

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