Leukocyte associated immunoglobulin-like receptor 1 modulates immune response to Staphylococcus aureus infection

Abstract Immunity is a balance of maximal pathogen defense with minimal host damage. Inhibitory immune receptors are important for maintaining this balance. We recently identified elevated levels of leukocyte-associated immunoglobulin (Ig)-like receptor protein1 (LAIR1), an inhibitory immune receptor, in cutaneous lymphoma patients, in whom invasive Staphylococcus aureus (S. aureus) infections are frequent. We therefore tested Lair1 knock-out (KO) mice in two models of invasive S. aureus infection: pneumonia and subcutaneous skin infection. In WT mice, skin infections resolve by 14 days post-infection (dpi), while pneumonia infections cause >50% lethality by 2dpi. In both models, Lair1 KO mice showed consistent patterns of myeloid hyper-activation. Lair1 KO had consistently larger skin lesions than WT throughout the 14 days, but no difference in bacterial clearance. Lair1 KO with pneumonia had higher survival (100% KO vs. 33% WT) despite comparable measures of lung injury and immune cell recruitment. In both models, KO mice produced higher levels of proinflammatory cytokines (IL-6, IL-1b) and neutrophil chemokines (CCL2, 3, 4) in lung, bronchoalveolar lavage, and skin by multiplex cytokine array. KO bone marrow-derived macrophages infected with S. aureus in vitro also secreted higher levels of proinflammatory cytokines (IL-6) and neutrophil chemokines (CCL2, 3, 4). Together, our results demonstrate that LAIR1 loss enhances myeloid activation, resulting in excessive tissue damage in skin infection, yet is protective against death in pneumonia. We posit that LAIR1 plays a crucial role in balancing myeloid immune response; LAIR1 activity can be beneficial or detrimental to the host depending on the site and type of infection.