Branched actin networks mediate macrophage-dependent host-microbiota homeostasis.

Branched actin networks formed by the Arp2/3 complex are essential for immune system function. Patients with loss-of-function mutations in the ARPC5 subunit of the Arp2/3 complex develop inflammation and immunodeficiency after birth, leading to early mortality. The basis for these phenotypes remains obscure. We found that loss of ARPC5, but not the ARPC5L isoform, in the mouse hematopoietic system caused early-onset intestinal inflammation after weaning. This condition was initiated by microbiota breaching the ileal mucosa and led to systemic inflammation. ARPC5-deficient macrophages and neutrophils infiltrated the ileum but failed to restrict microbial invasion. Specifically, macrophages that lack ARPC5 struggled to phagocytose and kill intracellular bacteria. Our results highlight the indispensable role of ARPC5-containing, but not ARPC5L-containing, Arp2/3 complexes in mononuclear phagocyte function and host-microbiota homeostasis.