Abstract
Differentiation of circulating monocytes into tissue-bound or tissue-resident macrophages is a critical regulatory process affecting host defense and inflammation. However, the regulatory signaling pathways that control the differentiation of monocytes into specific and distinct functional macrophage subsets are poorly understood. Herein, we demonstrate that monocyte-to-macrophage differentiation is controlled by the Protein Phosphatase, Mg2+/Mn2+-dependent 1A (PPM1A). Genetic manipulation experiments demonstrated that overexpression of PPM1A attenuated the macrophage differentiation program, while knockdown of PPM1A expression accelerated the ability of monocytes to differentiate into macrophages. We identify imiquimod and Pam3CSK4 as two Toll-like receptor agonists that induce PPM1A expression, and show that increased expression of PPM1A at the onset of differentiation impairs cellular adherence, reduces expression of inflammatory (M1) macrophage-specific markers, and inhibits the production of inflammatory cytokines. Our findings reveal PPM1A as a negative threshold regulator of M1-type monocyte-to-macrophage differentiation, establishing it as a key phosphatase that orchestrates this program.
Highlights
Cells of the mononuclear phagocyte system (MPS) are an integral part of the innate immune system with major roles in pathogen defense, inflammation, development, tissue integrity, and metabolic homeostasis[1,2,3]
Western blot analysis showed that PPM1A was kinetically upregulated in primary human monocyte derived macrophages (hMDM) up to 17-fold by day 11 post granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced differentiation relative to monocytes on day 0 (Fig. 1A)
While differentiation of primary monocytes is normally induced by stimulation with GM-CSF or M-CSF7, THP-1 monocytes differentiate into macrophages in response to Protein Kinase C agonists, such as Phorbol 12-myristate 13-acetate (PMA)[17,18] or byrostatin[19]
Summary
Cells of the mononuclear phagocyte system (MPS) are an integral part of the innate immune system with major roles in pathogen defense, inflammation, development, tissue integrity, and metabolic homeostasis[1,2,3]. The central dogma that tissue resident macrophages originate from circulating peripheral blood monocytes that migrate into tissues in response to various stimuli has been challenged by evidence that show these macrophages as being derived from embryonic precursors as well as having the ability for self-renewal[1,5,6] Despite these new findings, blood monocyte recruitment remains an important physiological process, in particular under conditions of inflammation, as local tissue resident macrophage numbers drastically decline due to emigration or cell death[1]. Blood monocyte recruitment remains an important physiological process, in particular under conditions of inflammation, as local tissue resident macrophage numbers drastically decline due to emigration or cell death[1] These infiltrating blood monocytes are the source of inflammatory macrophages as they undergo monocyte-to-macrophage differentiation. It remains unknown what regulates the intracellular signaling pathways during monocyte-to-macrophage differentiation to keep this process in check
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