Good Cop, Bad Cop: The Opposing Effects of Macrophage Activation State on Maintaining or Damaging Functional β-Cell Mass

Abstract

Loss of functional β-cell mass is a hallmark of Type 1 and Type 2 Diabetes. Macrophages play an integral role in the maintenance or destruction of pancreatic β-cells. The effect of the macrophage β-cell interaction is dependent on the activation state of the macrophage. Macrophages can be activated across a spectrum, from pro-inflammatory to anti-inflammatory and tissue remodeling. The factors secreted by these differentially activated macrophages and their effect on β-cells define the effect on functional β-cell mass. In this review, the spectrum of macrophage activation is discussed, as are the positive and negative effects on β-cell survival, expansion, and function as well as the defined factors released from macrophages that impinge on functional β-cell mass.

Keywords: cytokine; diabetes; islet; macrophage; β-cell.

Figure 1

Polarization of monocytes to M1-like or M2-like macrophages. Macrophages can be polarized along an activation spectrum in response to different signals within their microenvironment. An undifferentiated macrophage will lean more M1-like under proinflammatory conditions, propagating a “kill” response. Conversely, a macrophage may lean more M2-like under anti-inflammatory conditions usually following M1 damage where a “heal” response is necessary.

Figure 2

How the M1-like and M2-like extremes of the macrophage activation spectrum affect β-cell function, survival, and proliferation through secreted factors. M1-like macrophages are inflammatory in nature, producing and secreting inflammatory cytokines, NO, and ROS. M2-like macrophages play more of a protective role by inducing β-cell survival and proliferation. M2-like macrophages secrete anti-inflammatory cytokines, signaling peptides, and enzymes involved in tissue remodeling, inducing β-cell proliferation and enhancing insulin secretion.