Chicken heterophils as evolutionary models: insights into myeloperoxidase-independent antimicrobial strategies

The study of granulocytic phagocytes has been dominated by mammalian neutrophils, creating significant knowledge gaps in understanding functionally analogous granulocytes (heterophils) across vertebrate evolution. This review systematically examines chicken heterophils, comparing their biology to mammalian neutrophils to elucidate conserved and divergent molecular programs. Heterophils represent functionally analogous but mechanistically distinct antimicrobial effector cells characterized by fusiform granules and absence of myeloperoxidase (MPO) activity. Despite lacking MPO-dependent oxidative mechanisms, heterophils employ sophisticated non-oxidative strategies including cationic antimicrobial peptides, lysozyme, and heterophil extracellular traps (HETs). Transcriptional programs governing granulopoiesis show remarkable conservation across vertebrates, with C/EBP family transcription factors and G-CSF signaling maintaining core regulatory functions. However, comprehensive cross-species comparison between heterophils and neutrophils remains challenging, as molecular characterization of heterophil maturation and inflammatory programs has been difficult due to low recruitment numbers in conventional models. Genetically engineered chicken models now provide unprecedented opportunities for high-resolution analysis of heterophil subset diversity and inflammatory gene programs due to expanded myeloid populations. These advances position heterophils as ideal models for dissecting MPO-independent antimicrobial mechanisms and understanding primitive regulatory programs inherited from divergent comparator immune systems.