Neutrophil peptidylarginine deiminase 4 plays a systemic role in obesity-induced chronic inflammation in mice

Abstract

Background

Obesity is an increasing problem in our current society and is expected to keep rising in incidence. With its multiorigin, complex pathophysiology, it is difficult to treat and easy to acquire unnoticeably. During obesity, it has been established that the body is in a constant state of low-grade inflammation, thereby causing changes in immune cell physiology.

Objectives

Here, we investigated the influence of neutrophils, more specifically as a result of peptidylarginine deiminase 4 (PAD4) activity and the release of neutrophil extracellular traps (NETs), during obesity-induced chronic inflammation.

Methods

Wild-type mice were placed on a high-fat diet (HFD) and investigated over a period of 10 weeks for NET formation and its impact on the heart. Neutrophil-selective PAD4 knockout (Ne-PAD4^-/-) mice were studied in parallel.

Results

As a result of high fat intake, we observed clear alteration in the priming status of isolated neutrophils toward NET release, including early stages of speck formation and histone citrullination of apoptosis-associated speck-like protein containing a CARD. Ne-PAD4^-/- mice deficient in NET formation did not increase bodyweight to the same extent as their littermate controls, with Ne-PAD4^-/- mice being leaner after 10 weeks of HFD feeding. Interestingly, obesity progression led to cardiac remodeling and diastolic dysfunction in wild-type mice after 10 weeks, while this remodeling and subsequent decrease in function were absent in Ne-PAD4^-/- mice. Surprisingly, HFD did not alter NET content or thrombus formation in the inferior vena cava stenosis model.

Conclusion

Detrimental physiological effects, the result of obesity progression, can in part be attributed to neutrophil PAD4 and NETs in response to chronic inflammation.