Background Macrophage activation syndrome (MAS) is a rare and life-threatening disease, characterized by inappropriate activation of lymphocytes and histiocytes, leading to a cytokine storm, haemophagocytosis and multi-organ damage. Our previous studies demonstrated that the leukocyte immunoglobulin-like receptors A3 (LILRA3) plays a pathogenic role in multiple autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus and antiphospholipid syndrome. However, the role of LILRA3 in MAS has not been investigated. This study was undertaken to examine the in vivo role of LILRA3 in MAS model.

Methods To functionally study the role of LILRA3 in MAS pathogenesis, we generated a novel LILRA3 knock-in (LILRA3-KI) mouse. Human LILRA3 gene (Gene ID: 11026) was inserted into Rosa26 allele in C57BL/6 (B6) mice based on Cas9/sgRNA system. The MAS-like disease model was induced by repeated intraperitoneal injection of CpG-ODNs in either B6 wild-type (B6-WT) or LILRA3-KI mice. Mice were assessed for the development of splenomegaly, hematological indices, immune cellular response, cytokine expression, and spleen pathology.

Results Compared with untreated B6-WT control mice, both B6-WT and LILRA3-KI treated mice displayed decreased haemocytes; inappropriate activation of lymphocytes; increased organ damage; and elevated levels of cytokines. Notably, compared with CpG-ODN treated B6-WT mice, the treated LILRA3-KI mice displayed a less pronounced MAS-like phenotypes and immune responses, including an increase of erythrocytes, hemoglobin, and platelets; an expansion of CD4+ and CD8+ T cells; decreased spleen enlargement; less disorganized spleen architecture and inflammatory cell infiltration; and reduced serum levels of cytokines (IL-6, IL-10, IL-12p70, IL-18 and IFN-γ).

Conclusions Our data indicate that LILRA3 plays a protective role in MAS-like disease probably through suppressing the inappropriate activation of both CD4+ and CD8+ T cells, and subsequently leading to decreased production of cytokines, less haemophagocytosis and reduced spleen impairment.