Functional regulation of macrophages phenotype by SLIT3

Abstract

Slit homolog 3 protein (SLIT3)/roundabout (ROBO) receptor axis plays a critical role in nerve cell induction, vascular necrosis, embryonic development, bone remodeling, and tumor microenvironment. However, the functional role of this axis in regulation of macrophage phenotypes has not been elucidated yet. In the current study, lipopolysaccharides (LPS)-stimulated enhanced SLIT3 expression in macrophages. We found that LPS stimulated SLIT3 expression in bone marrow macrophages (BMMs) and in turn elevated SLIT3 led to enhancement of phagocytic capacity of these cells in vitro. On the other hand, SLIT3 deficiency skewed towards macrophage 1 (M1) profile accompanied by increase in the expression of pro-inflammatory cytokines. This phenotype is linked to increased NLR family pyrin domain containing 3 (NLRP3) and adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) in macrophages primed with LPS. Moreover, SLIT3-deficient mice displayed increased M1 population in peritoneal cells compared with that of wild-type mic followed by LPS administration in vivo. These findings suggest that the induction of SLIT3 may play an important role in the macrophage-associated inflammation, and thereby provide the potential treatment strategy for the excessive inflammation or sustained hyperinflammatory response.