Partners in crime: neutrophils and monocytes/macrophages in inflammation and disease

Abstract

Neutrophils are becoming recognized as highly versatile and sophisticated cells that display de novo synthetic capacity and potentially prolonged lifespan. Emerging concepts such as neutrophil heterogeneity and plasticity have revealed that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional characteristics. Indeed, these newly described neutrophil subsets will undoubtedly add to the already complex interactions between neutrophils and other immune cell types for an effective immune response. The interactions between neutrophils and monocytes/macrophages enable the host to efficiently defend against and eliminate foreign pathogens. However, it is also becoming increasingly clear that these interactions can be detrimental to the host if not tightly regulated. In this review, we will explore the functional cooperation of neutrophil and monocytes/macrophages in homeostasis, during acute inflammation and in various disease settings. We will discuss this in the context of cardiovascular disease in the form of atherosclerosis, an autoimmune disease mainly occurring in the kidneys, as well as the unique intestinal immune response of the gut that does not conform to the norms of the typical immune system.

Keywords: Atherosclerosis; Glomerulonephritis; Inflammation; Inflammatory bowel disease; Monocytes/macrophages; Neutrophils.

Fig. 1

Neutrophil–macrophage interaction during an immune response. Following pathogen recognition, tissue-resident M2 macrophages produce CXCL1 and tumor necrosis factor-alpha (TNF-α), which are involved in neutrophil recruitment and granulopoiesis. The recruited neutrophils destroy the invading pathogens and produce azurocidin that upregulates E-selectin and vascular cell adhesion molecule-1 (VCAM-1) expression on the endothelium to enhance monocyte recruitment. Monocytes that have transmigrated into the tissues differentiate into M1 macrophages and proceed to degrade the invading pathogens and produce granulocyte colony-stimulating factor (G-CSF) to prolong neutrophil survival. Once inflammation is resolved, M1 macrophages bind to neutrophils via TNF to induce apoptosis. Apoptotic neutrophils are cleared away by M1 macrophages that then polarize toward an M2 phenotype to restore homeostasis. (Stock images sourced from Servier Medical Art; Creative Commons)

Fig. 2

Immune interactions in atherosclerotic plaques. During atherosclerosis, neutrophils release granule proteins (GPs) that are deposited along the endothelial vessel to regulate the expression of cellular adhesion molecule (CAM). Monocytes traveling into the plaque differentiate into M1 macrophages and ingest surrounding LDLs causing their maturation to foam cells. Within the atherosclerotic plaques, GPs released from intralesional neutrophils interact with low-density lipoproteins (LDL), making them more recognizable to macrophages. GPs can also interact with monocytes, macrophages and foam cells to increase their proinflammatory, phagocytic activity. Concurrently, neutrophils can release their nuclear contents in the form of extracellular traps (NETs) to prime monocyte function causing the release of CXCL1 from monocytes, resulting in a positive feedback loop to enhance neutrophil recruitment. ROS reactive oxygen species; TNF tumor necrosis factor. (Stock images sourced from Servier Medical Art; Creative Commons)

Fig. 3

Intestinal homeostasis vs inflammatory bowel disease (IBD). During intestinal homeostasis, M2 macrophages mainly release anti-inflammatory factors that influence neutrophil phenotype and contribute to epithelium proliferation. Conversely, during IBD, the epithelial barrier of the intestines is damaged, which allows for the entry of microbes into the tissue. Subsequently, surrounding macrophages predominantly express the M1 macrophage phenotype and release pro-inflammatory factors involved in neutrophil recruitment. Neutrophils arrive at the site of injury and proceed to produce anti-microbial factors to control infection; however, they may also further contribute to tissue destruction. Neutrophil accumulation in the tissue can also occur due to impairment in neutrophil apoptosis. MIP-2 macrophage inflammatory protein 2; MPO myeloperoxidase; ROS reactive oxygen species; TGF-β transforming growth factor; VEGF vascular endothelial growth factor. (Stock images sourced from Servier Medical Art; Creative Commons)