Neutrophils in chronic inflammatory diseases

Abstract

Chronic inflammation is a component of many disease conditions that affect a large group of individuals worldwide. Chronic inflammation is characterized by persistent, low-grade inflammation and is increased in the aging population. Neutrophils are normally the first responders to acute inflammation and contribute to the resolution of inflammation. However, in chronic inflammation, the role of neutrophils is less well understood and has been described as either beneficial or detrimental, causing tissue damage and enhancing the immune response. Emerging evidence suggests that neutrophils are important players in several chronic diseases, such as atherosclerosis, diabetes mellitus, nonalcoholic fatty liver disease and autoimmune disorders. This review will highlight the interaction of neutrophils with other cells in the context of chronic inflammation, the contribution of neutrophils to selected chronic inflammatory diseases, and possible future therapeutic strategies.

Keywords: Chronic; Disease; Inflammation; Neutrophil; Neutrophil extracellular traps.

Fig. 1

Neutrophil crosstalk with cells in the circulation. Neutrophil interactions with platelets occur by direct adhesion through PSGL-1, integrin α_Lβ₂, and CD40 on neutrophils and P-selectin, ICAM-2 and CD40L on platelets. S100A8/A9 secreted by neutrophils promotes megakaryocyte proliferation and platelet production. Platelet secretion by PEVs containing chemokines and the release of chemokines from platelet granules activate neutrophils and promote NET formation. Conversely, NET proteins activate the coagulation cascade. Neutrophils promote B cell survival and differentiation to plasma cells through the secretion of BAFF, which binds to BCMA on B cells. Neutrophils can act as APCs to promote T cell differentiation in effector T cells through MHC molecules or inhibit T cell proliferation. Monocytes can extend the neutrophil lifespan and promote neutrophil recruitment through the secretion of GM-CSF and G-CSF. Monocyte recruitment is mediated by granule proteins released from neutrophils. Lactoferrin, azurocidin, S100A9, HPN1–3, LL-37 and NETs induce M1 macrophage polarization, while NETs, LL-37 and Anx1 induce M2 polarization. Anx1 annexin 1, APCs antigen presenting cells, BAFF B cell activating factor; BCMA, B cell maturation antigen, CD40L CD40 ligand, HNP1–3 human neutrophil peptides 1–3, ICAM intercellular adhesion molecule, MHC major histocompatibility complex, NET neutrophil extracellular trap, PEVs platelet extracellular vesicles, PSGL-1 P-selectin granulocyte ligand 1

Fig. 2

Neutrophil contributions to chronic disease. In obesity-related diseases, adipose tissue is infiltrated by neutrophils, where MPO and NE are released. Neutrophils promote macrophage infiltration through the secretion of IL1β by neutrophil-adipocyte direct interactions via CD11b-ICAM. In NAFLD, neutrophils infiltrate the liver, and ROS production leads to the activation of ASK and p38. The secretion of MPO promotes hepatocyte death and fibrosis, and hepatic NE and PR3 levels increase. miR-223, which is derived from neutrophils, inhibits the NLRP3 inflammasome. NETs lead to increased inflammation by recruiting monocytes/macrophages. These diseases are characterized by insulin resistance and inflammation. The autoimmune disease T1DM is characterized by neutrophil infiltration in the pancreas. β-cells of the islets release CXCL1 and 2, promoting neutrophil recruitment and infiltration. CXCL1 and 2 expression is induced by IL1β, which is secreted by macrophages. Neutrophils release NE and PR3 within the pancreas, increasing their levels. In the context of IBD, neutrophils can act either as beneficial players promoting pathogen clearance and wound healing through IL22 and NETs or as detrimental players enhancing inflammation via PAD4, proteases and ROS secretion. Cigarette smoke, the primary cause of COPD, inhibits apoptotic cell clearance while enhancing cell apoptosis. Chemokines released by alveolar macrophages induce neutrophil recruitment to the lung. NE and NETs trigger the transition of fibroblasts to myofibroblasts, leading to increased fibrosis. In addition, CTSG inhibits the IL22/IL22R pathway, increasing infection propensity. ASK apoptosis signal-regulating kinase, CTSG cathepsin G, CXCL CXC chemokine ligand, ICAM intercellular adhesion molecule, IL: interleukin, MPO myeloperoxidase, NAFLD nonalcoholic fatty liver disease, NE neutrophil elastase, NLRP3 NOD-, LRR- and pyrin domain-containing protein 3, PAD4 peptidyl arginine deiminase 4, ROS reactive oxygen species, T1DM type 1 diabetes mellitus