Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity

Abstract

Macrophages and neutrophils are key components involved in the regulation of numerous chronic inflammatory diseases, infectious disorders, and especially certain autoimmune disease. However, little is known regarding the contribution of these cells to the pathogenesis of autoimmune disorders. Recent studies have aimed to clarify certain important factors affecting the immunogenicity of these cells, including the type and dose of antigen, the microenvironment of the cell-antigen encounter, and the number, subset, and phenotype of these cells, which can prevent or induce autoimmune responses. This review highlights the role of macrophage subsets and neutrophils in injured tissues, supporting their cooperation during the pathogenesis of certain autoimmune diseases.

Keywords: Autoimmune disease; Autoimmunity; Inflammation; Macrophages; Neutrophils.

Fig. 1

Origin and development of macrophages and neutrophils. a The generation of macrophages is dependent on hematopoietic growth factor receptor Csf1r (c-fms, M-CSFR, CD115). The known ligands of Csf1r, Csf1/M-CSF and interleukin (IL)-34 are likely both important for the development of the mononuclear phagocyte lineage. On the other hand, hematopoietic cytokines as granulocyte–macrophage colony-stimulating factor (GM-CSF) and granulocyte colony stimulating factor (GCSF) that promote neutrophil progenitor proliferation and differentiation. b Bone marrow neutrophil lineage cells can be divided into three compartments: the stem cell pool (stem cells and pluripotent progenitors), the mitotic pool and the post-mitotic pool. c The regulation of Neutrophil egress from de bone marrow by CXCR4 and CXCR2 chemokine ligands, where stromal cells produce C-X-C-motif chemokine ligand (CXCL) 12 that binds to C-X-C-motif chemokine receptor (CXCR) 4, leading to neutrophil retention, while release is mainly mediated by CXCR2. Hematopoietic stem cell (HSC), common myeloid progenitor (CMP), granulocyte–macrophage progenitor (GMP), myeloid progenitor (MP)

Fig. 2

Schematic representation of macrophage activation and polarization. Classically polarized macrophages (M1 macrophages) are activated by LPS, IFN-ƴ and TNF-α. M1 cells have high microbicidal activity, immune-stimulatory functions and tumour cytotoxicity. Alternatively polarized macrophages (M2 macrophages) are involved with anti-inflammatory, wound repair and tumour promotion. M2 macrophages can be further divide into M2a, M2b, and M2c macrophages. IL-4 and IL-13 always activate macrophages to be M2a, while M2b are activated by immune complexes (ICs), TLRs, or IL-1ra. Finally, M2c macrophages are polarized by IL-10, TGF-β or glucocorticoids. All of the phenotypes express a series of different cytokines, chemokines and receptors

Fig. 3

Neutrophil extracellular traps. Neutrophil extracellular traps (NETs) are composed of nuclear components (such as DNA and histones) and are decorated by proteins from primary granules (such as myeloperoxidase and neutrophil elastase), secondary granules (such as lactoferrin and pentraxin 3), and tertiary granules. NETs have been shown to trap microorganisms. Initially, the neutrophils become rounded with uniformly condensed chromatin, occurs because of PAD-4-mediated citrullination of histones, and then undergo nuclear envelope breakdown so DNA-containing vesicles eventually fuse with the plasma membrane, and NETs are released to trap microorganism. NETs can cause development of autoimmune disorders trough molecules present in the NET or the degradation products of NETs by DNAse I can act as auto-antigen or because excessive formation of degradation failure of NETs. Font: Adapted by [71], Mantovani et al. [72] and Phillipson and Kubes [245]

Fig. 4

Major mechanism of action of neutrophils and macrophages in type 1 diabetes and rheumatoid arthritis

Fig. 5

A simplified schematic of the crosstalk between neutrophils/macrophages in rheumatoid arthritis

Fig. 6

A simplified schematic of the role of macrophage/neutrophil in autoimmune diseases type 1 diabetes and rheumatoid arthritis