Beyond inflammation: the multifaceted therapeutic potential of targeting the CXCL8-CXCR1/2 axis in type 1 diabetes

Abstract

Identifying novel therapeutic targets involved in the multiple mechanisms underlying the complex pathophysiology of type 1 diabetes (T1D) could change the natural history of this disease. The CXCL8-CXCR1/2 axis is emerging as a therapeutic target with a crucial, multifaceted role in T1D pathophysiology. CXCL8-dependent neutrophil chemotaxis to the pancreas precedes autoimmunity, and CXCR1/2 blockade mitigates insulitis and T1D development in preclinical models. In parallel, CXCL8 can act in a β cell-autonomous manner, and exert non-immune actions on adipocytes, hepatocytes, podocytes, and muscle cells that contribute to insulin resistance and diabetic complications. In this review, we delineate compelling evidence of immune and non-immune actions of the axis in the onset and progression of T1D. We show that the CXCL8-CXCR1/2 axis represents a promising therapeutic target for the prevention/reversal of T1D, with a meaningful potential clinical advantage conveyed by its role in multiple components of the pathology and diabetic complications.

Keywords: CXCL8; CXCR1; CXCR2; chemokines; inflammation; interleukin-8; neutrophils; type 1 diabetes.

Figure 1

Immune actions of the CXCL8-CXCR1/2 axis in T1D. (a) Macrophage- and β cell-derived CXCL8 induces neutrophil and possibly autoreactive T cell chemotaxis to the pancreas. (b) CXCL8 initiates a positive feedback loop, mostly propagated by recruited neutrophils and macrophages, which exacerbates and amplifies insulitis with the release of additional proinflammatory mediators. (c) Neutrophil NETosis activates IFNα-producing pDCs. Specifically, the release of NET-derived CRAMP complexes with β cell debris and dsDNA (self-DNA) and activates IFNα-producing pDCs which serve as antigen-presenting cells. (d) PNAs contribute to a positive feedback loop of platelet – neutrophil activation, which is linked to NETosis and, subsequently, promotes autoantibody production via NETosis ultimately leading to T cell activation.

Figure 2

Non-immune actions of the CXCL8-CXCR1/2 axis in T1D. (a) Adipocyte CXCR1/2 signaling reduces glucose transport and disrupts metabolism by downregulating the surface expression of glucose transporters, GLUT4 and GLUT1. Adipocyte CXCR2 activation can drive adipogenesis, further amplifying these effects. (b) Muscle cell CXCR2 receptors influence insulin-stimulated glucose transport, with CXCL5-CXCR2 activation shown to reduce glucose transport. (c) Hepatocyte CXCR1/2 activation facilitates inflammation-induced insulin resistance and inflammation-induced reductions in GLUT transporters/glucose transport on hepatocytes. (d) β cell ER stress is sufficient to induce β cell dysfunction, apoptosis, overexpression of MHCI/II and the release of proinflammatory mediators, including CXCL8, which facilitate further β cell ER stress and promote islet-specific autoimmunity. Importantly, β cell debris can serve as autoantigen material. (e) CXCL1- and CXCL5- activation of CXCR2 impairs β cell function (e.g., insulin secretion pathways) by affecting intracellular calcium dynamics in pancreatic islets.

Figure 3

Stage-specific combination therapy strategies for T1D. CXCL8-targeting therapies show promise to improve outcomes across the stages of T1D, with evidence of CXCL8-CXCR1/2 axis involvement throughout the course of disease progression. In presymptomatic T1D, CXCR1/2 blockade may mitigate insulitis and β cell stress which could otherwise initiate autoimmunity. In new-onset T1D, CXCR1/2 blockade may mitigate or slow the progression of T cell migration to the pancreas and T cell-mediated autoimmune destruction of β cells. In late T1D, CXCR1/2 blockade may improve outcomes related to diabetic complications. When administered in combination with existing therapies developed for various stages of the disease, CXCL8-targeting therapies could improve outcomes. Anti-inflammatory agents, such as TNF- or JAK- inhibitors, and antigen-specific therapies (e.g., GAD-alum, oral insulin, multiple islet peptides) are developed for early presymptomatic T1D prior to the loss of β cells. Immunomodulating agents targeting T cells or B cells (e.g., anti-IL-21, anti-CD3, anti-CD80, anti-CD86, anti-CD20, and antithymocyte globulin [ATG]) and Treg-targeting agents (e.g., low-dose IL-2, Treg cell therapy) have shown promise to delay the onset or slow the progression of T1D through the development of Stage 3 T1D and are developed for Stage 1 up to Stage 3. Therapeutic strategies aiming to preserve or expand β cell mass/function (e.g., glucagon-like peptide 1 [GLP1] receptor agonists, calcium channel blockade [verapamil], monoamine oxidase A [MAOA] inhibition [harmine], and bone morphogenetic protein-7 [BMP-7]) are developed for Stage 2–3 T1D. For late-stage T1D, β cell replacement strategies and/or sodium-glucose transport protein 2 (SGLT2) inhibitors are being tested, with the aim to address pathologies driving severe diabetic complications associated with this stage of T1D.

Figure 4

The potential for CXCR1/2-targeting disease-modifying therapies. The CXCL8-CXCR1/2 axis plays a crucial role in T1D onset and progression, acting through immune (e.g., neutrophils) and non-immune (e.g., β cells, adipocytes) pathways, such that CXCR1/2-targeting therapies represent a multifaceted treatment approach.