Age-dependent differences in efferocytosis determine the outcome of opsonophagocytic protection from invasive pathogens

• Published in: Immunity (Cambridge, Mass.) Mass.), 2023-06, Vol.56 (6), p.1255-1268.e5
• Main Authors: Bee, Gavyn Chern Wei, Lokken-Toyli, Kristen L., Yeung, Stephen T., Rodriguez, Lucie, Zangari, Tonia, Anderson, Exene E., Ghosh, Sourav, Rothlin, Carla V., Brodin, Petter, Khanna, Kamal M., Weiser, Jeffrey N.
• Format: Article
• Language: English
• Subjects: Animals; c-Mer Tyrosine Kinase; CD11b; complement; early-life immunity; efferocytosis; Humans; invasive infection; macrophages; Macrophages - metabolism; Mice; myeloid development; Neutrophils; opsonophagocytosis; Phagocytosis; streptococci; Streptococcus pneumoniae
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2023.03.018

In early life, susceptibility to invasive infection skews toward a small subset of microbes, whereas other pathogens associated with diseases later in life, including Streptococcus pneumoniae (Spn), are uncommon among neonates. To delineate mechanisms behind age-dependent susceptibility, we compared age-specific mouse models of invasive Spn infection. We show enhanced CD11b-dependent opsonophagocytosis by neonatal neutrophils improved protection against Spn during early life. The augmented function of neonatal neutrophils was mediated by higher CD11b surface expression at the population level due to dampened efferocytosis, which also resulted in more CD11bhi “aged” neutrophils in peripheral blood. Dampened efferocytosis during early life could be attributed to the lack of CD169+ macrophages in neonates and reduced systemic expressions of multiple efferocytic mediators, including MerTK. On experimentally impairing efferocytosis later in life, CD11bhi neutrophils increased and protection against Spn improved. Our findings reveal how age-dependent differences in efferocytosis determine infection outcome through the modulation of CD11b-driven opsonophagocytosis and immunity. [Display omitted] •Neonates resist Streptococcus pneumoniae invasive infection•Neonatal neutrophils have enhanced opsonin C3-integrin CD11b-dependent phagocytosis•Dampened efferocytosis increases CD11bhi aged neutrophils during early life•Dependence on CD11b opsonophagocytosis predicts age-related patterns of infection Many pathogens rarely cause invasive diseases during neonatal life. Bee et al. delineate an immunologic determinant of this phenomenon. During early life, developmental impairments in macrophage function (efferocytosis) alter neutrophil homeostasis to augment CD11b-dependent opsonophagocytosis. This results in increased protection against certain pathogens and accounts for age-related patterns of susceptibility.