Macrophage functional phenotype can be consecutively and reversibly shifted to adapt to microenvironmental changes.

Macrophages are functionally plastic cells, and have developed distinct functional subsets in associa-tion with cancer, autoimmune disease, and chronic infections. As an alternative to the concept of subset development, we hypothesized that macrophages, in response to changes in their tissue environment, can reversibly and progressively change the pattern of functions that they express. We examined the reversible and progressive shift of functional phenotypes of macrophages in response to changes in their tissue environment. As demonstrated herein, macrophages can reversibly shift their functional patterns in response to sequential changes in cytokine environment. After treatment alone or alternative with IL-4, MFCS, IL-12, INF-γ or LPS, the cells showed various functional patterns. A progression through multiple functional phenotypes was displayed after sequential treatment of macrophages with multiple cytokines. This ability to adapt to changing cytokine microenvironments has significant relevance in vivo, as evidenced by the fact that developed macrophage functional phenotypes in vivo in aged mice or forestomach carcinoma (MFC) tumor-bearing mice can be shifted by modifying their microenvironment. Therefore, a concept of shifted macrophage functional phenotypes has important implications for therapeutic targeting of macrophages in chronic diseases. The dominance of particular functional phenotypes of macrophages in chronic diseases may play an important role in pathogenesis.