Critical role of the Mac1/NOX2 pathway in mediating reactive microgliosis-generated chronic neuroinflammation and progressive neurodegeneration

Abstract

As average life expectancy rises throughout the world, neurodegenerative diseases have emerged as one of the greatest global public heath challenges in modern times. Substantial efforts have been made in researching neurodegenerative diseases over the last few decades, yet their predominantly sporadic nature has made uncovering their etiologies challenging. Mounting evidence has suggested that factors like damage-associated molecular patterns (DAMPs) released by stressed and dying neurons are likely involved in disease pathology and in stimulating chronic activation of microglia that contributes to neuronal oxidative stress and degeneration. This review focuses on how the microglial integrin receptor Mac1 and its downstream effector NADPH oxidase (NOX2) contribute to maintaining chronic neuroinflammation and are crucial in inflammation-driven neurotoxicity in neurodegenerative diseases. Our hope is to provide new insights on novel targets and therapies that could slow or even halt neurodegeneration.

Figure 1

Reactive microgliosis drives chronic and progressive neurotoxicity. Microglia can initiate neurotoxicity by recognizing pro-inflammatory stimuli, such as cytokines, pathogen associated molecular patterns (PAMPs) from microbial pathogens to become activated and producing cytotoxic factors to damage neurons. Damage-associated molecular patterns (DAMPs) released from damaged/dead neurons can sustain microglia activation (reactive microgliosis), which cause further neuronal damage/death. Microglia Mac1 could recognize DAMPs and activate downstream NADPH oxidase (NOX2) to produce superoxide anions and its associated reactive oxygen species (ROS), such as hydrogen peroxide, which play a critical role in reactive microgliosis and driving the chronic neurodegeneration.

Figure 2

Inflammation-derived oxidative stress leads to a vicious cycle inside the damaged neurons and causes neuronal death. Sustained release of neurotoxic factors from activated microglia continually bombards neurons and increases neuronal oxidative stress during chronic neuroinflammation. The oxidative stress causes mitochondria dysfunction, which could upregulate the expression of neuronal NOX, produce more ROS and lead to progressive neurodegeneration.

Figure 3

The novel promising anti-inflammatory therapies. The conventional therapies target a limited number of pro-inflammatory factors and failed to block disease progression. The novel anti-inflammatory therapy targets upstream neuro-inflammatory signaling by inhibiting microglial NOX2, which in turn reduces superoxide production and over-activation of microglia and thereby reducing the release of most pro-inflammatory and detrimental factors.