IL-36 receptor agonist and antagonist imbalance drives neutrophilic inflammation in COPD

Abstract

Current treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating alternative therapies. Here, we show that COPD subjects have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared to control subjects. IL-36γ is derived from small airway epithelial cells (SAEC) and further induced by a viral mimetic, whereas IL-36RA is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralizing antibody could be a promising new therapeutic strategy in the treatment of COPD.

ERS International Congress 2023: highlights from the Basic and Translational Sciences Assembly

“…Returning to COPD, O wles et al . [ 102 ] focused on IL-36γ and its effects on lung macrophages [ 103 ]. Supernatants from IL-36γ-stimulated small airway fibroblasts were exposed to monocyte-derived macrophages.…”

“…However, spatially distinct cell niches were revealed. Eosinophils and type 2 inflammatory features were linked with basophils, indicating spatial correlation [ 103 ]. This patchy pattern of immune cell niches results in a complex mix of inflammatory signatures, which impacts treatment effectiveness [ 106 ].…”

Emerging functions and therapeutic targets of IL‐38 in central nervous system diseases

“…[7][8][9][10][11][12][13] Of further note, IL-36 receptor antagonist (IL-36Rα) and IL-38, two anti-inflammatory cytokines with similar functions in IL-1F reduced neuronal death and improved cognitive function defects by down-regulating the expression levels of IL-1β, tumor necrosis factor α (TNFα), and IL-6. 14,15 Therefore, targeting inflammatory cytokines is a promising new therapy for the treatment of CNS diseases and injuries. IL-38 is a newly discovered cytokine in the IL-1 family and plays an important role in a variety of diseases, including but not limited to CNS diseases.…”

“…After effective anti‐inflammatory treatment, the expression levels of these cytokines were remarkably reduced, and cognitive dysfunction was effectively improved 7–13 . Of further note, IL‐36 receptor antagonist (IL‐36Rα) and IL‐38, two anti‐inflammatory cytokines with similar functions in IL‐1F reduced neuronal death and improved cognitive function defects by down‐regulating the expression levels of IL‐1β, tumor necrosis factor α (TNF‐α), and IL‐6 14,15 . Therefore, targeting inflammatory cytokines is a promising new therapy for the treatment of CNS diseases and injuries.…”

Innate Immune Reprogramming in Chronic Obstructive Pulmonary Disease: New Mechanisms for Old Questions

“…The alveolar macrophage is an innate immune cell best known for its phagocytic functions, especially in the context of infection. It is often overlooked because immunology is a rapidly advancing field, with mediators like IL-36 ( 1 ) and cells like type 2 innate lymphoid cells ( 2 ) being relatively recent discoveries. However, the lung macrophage family members are critical innate immune cells that can drive pathophysiological processes in respiratory diseases and, in particular, have been demonstrated as integral to the pathobiology of chronic obstructive pulmonary disease (COPD).…”