Adjusting Macrophage Polarization for Therapeutic Effects is not Straightforward

The innate immune cells known as macrophages can adopt different packages of behaviors, known as polarizations, under different circumstances. The underlying reality is more a continuum than two clear categories, but researchers classify macrophages as being either M1, aggressive and inflammatory, or M2, pro-regenerative and anti-inflammatory. In theory, a number of issues that manifest with age could be slowed or reversed by forcing M1 macrophages to adopt M2 behaviors instead. The open access paper here is chiefly interesting for the discussion on why this is far from simple: a blunt approach to reprogramming macrophages is certainly feasible, but will probably do as much harm as good.

Compared to the classical phagocytotic "M1" macrophages, the alternatively polarized macrophages, called "M2" macrophages, function as modulators of cellular and humoral immunity and as mediators of tissue repair and remodeling. Transforming growth factor beta 1 (TGFβ1) is the most important growth factor enhancing tissue repair and fibrosis, and is believed to be produced and released by a subpopulation of M2 macrophages (M2c) in response to IL-10, in contrast to M2a macrophages which are primarily anti-inflammatory.

Prior work has shown that macrophages are the only inflammatory cells that infiltrate into the closed nucleus pulposus, and the number of macrophages is positively correlated with the severity of intervertebral disc degeneration. Moreover, there is evidence to suggest that macrophages may either directly play a role in phagocytosis, or synergistically regulate lumbar disc metabolism through a neuro-immune mechanism. Likewise, macrophage dysfunction can cause the aggregation, chemotaxis, and diffusion of inflammatory factors, leading to degradation of the extracellular matrix in the intervertebral disc, which in turn leads to lumbar disc degeneration. However, whether macrophage polarization is critical for the development of lumbar disc degeneration (LDD) and by what mechanism it may affect LDD, remains to be experimentally tested. This question was addressed in the current study.

The delicate phenotypic control of tissue macrophages is critical for proper tissue repair after injury and is very time-sensitive. Too much M1 polarization results in severe inflammatory responses, severe tissue damage and poor recovery. However, too much M2 polarization may result in insufficient inflammatory responses and incomplete pathogen- and cell debris removal. Importantly, M2-like polarization induces fibrosis, mainly mediated by TGFβ signaling.

In the current study, we co-blocked DNMT1 and TGFβ1 in macrophages. While DNMT1 suppression induced a general M2-like polarization in macrophages, specific inhibition of TGFβ1 may affect IL-10 production and secretion, which in turn reduces the generation of fibrotic M2c macrophages. Our results showed that co-blocking TGFβ1 did not attenuate the effects of DNMT1 inhibition on induction of M2-like macrophage polarization, but did reduce cell apoptosis and pain-associated MMP1, thereby promoting a favorable therapeutic outcome.

Link: https://doi.org/10.18632/aging.102909

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