A neuropeptide, Substance-P, directly induces tissue-repairing M2 like macrophages by activating the PI3K/Akt/mTOR pathway even in the presence of IFNγ

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.

Impaired functional capacity of polarised neonatal macrophages

“…Engagement of CD163 initiates PI3k/AKT signaling, which, again, leads to IL10 secretion by the cell [24][25][26] . PBMΦ-0 and CBMΦ-0 showed no significant differences in IL-10 secretion after co-cultivation with EL (Fig.…”

Neuro-immune crosstalk and allergic inflammation

“…These neuropeptides directly act on various immune cells ( Figure 1). Substance P is known to be a proinflammatory neuropeptide that activates multiple immune cells, including T cells, macrophages, DCs, mast cells, eosinophils, and neutrophils (19)(20)(21). The functions of VIP and CGRP skew toward a Th2 cytokine-like phenotype.…”

Substance P Improves Renal Ischemia Reperfusion Injury Through Modulating Immune Response

“…However, one of the subtypes of M2 macrophages, M2a, is distributed in segmental glomerulosclerosis and tubular atrophy/interstitial fibrosis in IgA nephropathy patients and correlated with their severity (56). Interestingly, Lim et al demonstrated that SP is an environmental factor that determines the polarization of macrophages and mediates SP-specific M2 polarization with M2c function but with M2a markers (19). Therefore, further studies will be needed on the role and subtypes of SP-induced specific M2 macrophages in diverse kidney diseases.…”

“…In the case of ischemia reperfusion injury (IRI), SP improves the injury by increasing MSC and endothelial progenitor cell (EPC) in the blood circulation and reducing TNFα (18). Furthermore, SP directly participates in the transition between M1 macrophages and M2 macrophages (19). However, SP expression has not been investigated in kidney disease, and whether SP has a beneficial effect on AKI is unclear.…”