ROLE OF P50 NF-KB IN MACROPHAGE MIGRATION

Tumor Associated Macrophages (TAM) and lipopolisaccharide- (LPS)-tolerant macrophages share several characteristics, such as a massive accumulation of the p50 NF-B homodimer in the nucleus and the incapacity to express strong inflammatory programs (eg. impaired TNF production) in response to inflammatory signals such as LPS (tolerance). Our recent study has described that both TAM and LPS-tolerant macrophages express an M2 polarized phenotype, associated with strong anti-inflammatory and immunosuppressive functions. Due to the high capability of TAM to infiltrate solid tumors, here we investigated the effect of tolerance on macrophage migration, in vitro and in vivo. Our study shows that LPS-tolerant macrophages maintain their capacity to respond to the chemotactic C5a complement factor, in terms of both cell migration and ERK1/2 phosphorylation. In contrast, LPS-tolerant macrophages did not respond to the chemokines CCL2 and CCL5. By using the air pouch model in mice treated systemically with LPS (in vivo tolerance) we further demonstrated a differential regulation of different leukocyte populations recruitment. In particular, a F4/80high-C5aR (CD88)high macrophage population was still recruited in response to C5a, in the air pouch of LPS-tolerant mice, supporting the functional activity of this pathway in in vivo tolerant conditions. Similarly, also tumor associated macrophages (TAM) are F4/80high-CD88high, showed ERK phosphorylation and chemotactic ability only in response to C5a. Future studies in our group will address the role of tolerance in driving selective accumulation of distinct polarized macrophage populations in pathological sites (eg. cancer, chronic inflammatory diseases). We speculate that selective recruitment of tolerant M2 populations may contribute to the extinction of the inflammatory response, thus contributing to restoring tissue homeostasis.