Abstract
Macrophage polarization plays an important role in tissue damage and repair. In this study, we show that Substance-P (SP) can directly induce M2 polarization of inflammatory macrophages. SP induced the differentiation of GM-CSF-differentiated pro-inflammatory macrophages into alternatively activated phagocytic M2 like macrophages (M2SP) through direct activation of the PI3K/Akt/mTOR/S6kinase pathway and induction of Arginase-1, CD163, and CD206, all of which were nullified by pretreatment with the neurokinin-1 receptor (NK-1R) antagonist RP67580 and specific signaling pathway inhibitors. M2SP were distinct from IL-4/IL-13-induced M2a and IL-10-induced M2c subtypes; they did not show STAT activation and exhibited high phagocytic and endothelial adhesive activity. Furthermore, SP had a dominant effect on M2 polarization over Interferon gamma (IFNγ), a potent M1-skewing cytokine, and effectively induced the M2 phenotype in monocytes and the human THP-1 cell line. Finally, adoptively transferred M2SP migrated to a spinal cord injury (SCI) lesion site and improved functional recovery. Collectively, our findings show that SP, a neuropeptide, plays a role as a novel cytokine by inducing tissue-repairing M2SP macrophages and thus may be developed for pharmacological intervention in diseases involving chronic inflammation and acute injury.
Highlights
Macrophages are essential components of the innate and adaptive immune systems and play central roles in inflammation and host defense[1, 2]
We explored whether SP can directly induce M2 type macrophages from bone marrow-derived monocytes, Granulocyte macrophage colony stimulating factor (GM-CSF)-differentiated macrophages similar to inflammatory macrophages, and the THP-1 human monocytic cell line based on the expression of M1 and M2 subtype-specific markers such as Arginase-1, inducible NO synthase (iNOS), CD163 scavenger receptor, CD206 mannose receptor, CCR7, CD68, and STAT phosphorylation
The samples derived from the same experiment and full-length blots are presented in Supplementary Figure 22 (n = 2). (i) Treatment of functional blocking antibodies to IL-10 and IL-6 failed to block SP-induced CD163 expression at 3 d (Green = CCR7, Red = CD163, Blue = DAPI) (n = 3). (j) Schematic representation of Arginase-1+CD163+ M2 polarization in response to SP via neurokinin-1 receptor (NK-1R)/phosphatidylinositol 3 kinase (PI3K)/Akt/mTOR/ S6K activation
Summary
Macrophages are essential components of the innate and adaptive immune systems and play central roles in inflammation and host defense[1, 2] These cells are functionally classified into two major types: classically activated, proinflammatory (M1) macrophages and alternatively activated (M2) macrophages[3, 4]. In tissue repair, M2 macrophages may terminate tissue-destructive proinflammatory responses but create a reparative environment by cleaning up apoptotic dead cells and stimulating angiogenesis and cell proliferation This event seems to be an important step toward the acquisition of tolerance to self-antigens of apoptotic cells and avoidance of the induction of an autoimmune response, especially in IL-10-induced deactivating M2c-type www.nature.com/scientificreports/. Dose-dependent increased activity and expression of Arginase-1 determined after 6 h of SP treatment. Many intracellular signaling pathways and cellular metabolic states act together during M2 polarization
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